Capillary rarefaction from the kidney point of view

Capillary rarefaction from the kidney point of view Capillary rarefaction is broadly defined as a reduction in vascular density. Capillary rarefaction in the kidneys is thought to promote hypoxia, impair hemodynamic responses and predispose to chronic kidney disease (CKD) progression and hypertension development. Various mechanisms have been suggested to play a role in the development of capillary rarefaction, including inflammation, an altered endothelial-tubular epithelial cell crosstalk, a relative deficiency in angiogenic growth factors, loss of pericytes, increased activity of Transforming growth factor -b1 and thrombospondin-1, vitamin D deficiency, a link to lymphatic neoangiogenesis and INK4a/ARF (Cylin-dependent kinase inhibitor 2a; CDKN2A). In this review, we summarize the tools available to monitor capillary rarefaction noninvasively in the clinic, the contribution of capillary rarefaction to CKD and hypertension, the known mechanisms of capillary rarefaction, and potential future strategies to attenuate capillary rarefaction and reduce its negative impact. Therapeutic strategies to be explored in more detail include optimization of antihypertensive therapy, vitamin D receptor activators, sirtuin 1 activators, Hypoxia inducible factor prolyl hydroxylase inhibitors and stem cell therapy. Key words: capillary, chronic kidney disease, hypertension, hypoxia-inducible factor, pericyte, rarefaction thought to promote hypoxia, impair hemodynamic responses Introduction and potentially predispose to chronic kidney disease (CKD) pro- Emerging evidence suggests that the kidney has considerable gression and hypertension development [1]. In this review, we capacity to repair and regenerate. However, not all kidney cell summarize the tools available to monitor capillary rarefaction types have the same regenerative capacity. Unlike proximal noninvasively in the clinic, the role of capillary rarefaction in tubule cells, cells of the renal vasculature have a poor capacity the progression of CKD and the development of hypertension, for repair, which may lead to a persistent reduction in vascular the known mechanisms of capillary rarefaction, and potential density following an acute or chronic insult. The reduction in future strategies that attenuate capillary rarefaction and its vascular density is broadly termed ‘capillary rarefaction’ and is negative impact on CKD and hypertension. Received: July 11, 2017. Editorial decision: October 4, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 296 | B. Afsar et al. capillary rarefaction were observed before the onset of overt fib- Noninvasive in vivo assessment of capillary rosis and may be the earliest diagnostic and prognostic sign for rarefaction renal dysfunction. At histological level, CKD progression is asso- In kidney biopsy specimens, capillary rarefaction is assessed ciated with evidence of capillary injury, such as focal widening histologically. However, kidney biopsy is an invasive procedure, of the subendothelial space and higher numbers of endothelial not suitable for future clinical trials assessing the impact of vacuoles and caveolae, reduced numbers of endothelial fenes- therapeutic intervention on capillary rarefaction. Noninvasive trations and increased thickness of the cell soma and lamina quantitative analyses such as nailfold capillaroscopy a com- densa of the capillary basement membrane, and increased per- puted tomography (CT) are alternatives more suitable for meability [15]. repeated assessment in the clinic, the latter marred by radiation and contrast use, but allowing direct quantification of kidney Capillary rarefaction and hypertension vascular rarefaction. Dermal capillaries represent an ‘open’ and representative Capillary rarefaction has also been implicated in the pathogenesis window for the in vivo study of the human microcirculation that of essential hypertension. The pathogenesis of capillary can be directly, repetitively and easily visualized by noninvasive rarefaction in hypertension is unknown, but it may involve a low- techniques such as nailfold capillaroscopy to show capillary rar- grade inflammatory response [18, 19]. In spontaneously hyperten- efaction [2, 3]. However, visual inspection of the capillaries is sive rats, there is rarefaction of arterioles and capillaries in skeletal limited by the depth of penetrance of light photons and pro- muscles [20]. Additionally, the number of nailfold capillaries is vides only a one-dimensional analysis of a three-dimensional lower in patients with untreated essential hypertension than in problem. controls [21]. In the non-renal population of hypertensive and nor- Functional in vivo micro-CT imaging has allowed accurate motensive individuals, capillary density significantly correlated assessment of vessel dysfunction in preclinical CKD [4]. with high-density lipoprotein/low-density lipoprotein ratio, but Furthermore, small-caliber artery rarefaction (interlobular not with serum vascular endothelial growth factor (VEGF) or with artery and more distal branches) can be followed separately high-sensitivity C-reactive protein. An inverse association was from capillary rarefaction [4]. In humans, contrast-enhanced CT found with body mass index, insulin levels and homeostasis angiography has also been used to assess kidney vascular rare- model assessment-insulin resistance [22]. faction by quantifying renal blood volume. Renal blood volume In essential hypertension, capillary rarefaction was associated was lower in the cortex of CKD patients than in controls and with cardiovascular reactivity and exercise-induced rheological closely mirrored capillary rarefaction in the corresponding abnormalities. In all, 61 men with essential hypertension and nephrectomy specimens. In patients with follow-up CT angiog- capillary rarefaction (<80 capillaries per field), and 20 age- and raphy, reduction of renal function was paralleled by a decline in sex-matched controls underwent a strenuous cycle ergometer renal blood volume [5]. test to monitor, during exercise and recovery, the blood pressure profile, the hemorheological pattern and other parameters. Capillary rarefaction and CKD progression Hypertensive men with <72 capillaries per field had an abnormal hemorheological profile before exercise. The physiological The major branches of the renal artery conduct more than 90% response to exercise was observed only in controls and in hyper- of renal blood flow directly to the glomerular capillary bed tensives with >73 capillaries per field. Abnormal responses to located in the kidney cortex [6]. Then, the efferent arteriole exercise worsened as capillaries were more rarefied [23]. branches into peritubular capillaries, which initially supply oxy- Finally, hypertension is a frequent side effect of anti- gen and nutrients to the highly metabolically active proximal angiogenesis therapy targeting VEGF receptor signaling in can- tubular cells. Less than 10% of the arterial blood flow is deliv- cer patients, to the point that development of hypertension ered to the medulla and then to more profound parts of the implies adequate VEGF inhibition and is associated with nephron. As a result, the cortex pO is between 30 and 50 improved tumor responses [24]. In this regard, the receptor tyro- mmHg, while in the medulla and medullary rays it is 10–20 sine kinase sunitinib promoted dermal capillary rarefaction and mmHg, the lowest in the body [7, 8]. Thus, even under physio- this could be one of the mechanisms for hypertension develop- logical circumstances, tubular cells, especially in some parts of ment in these patients [25]. the nephron, are relatively hypoxic. It is meaningful that erythropoietin-producing cells reside in the kidney, where they can sensitively detect hypoxia due to anemia. Under pathologi- Mechanisms of capillary rarefaction cal circumstances, the hypoxic areas may extend even into cor- Recent evidence has identified various mechanisms that con- tex region [9]. In this regard, peritubular capillary rarefaction is tribute to the development of capillary rarefaction (Figure 1). a hallmark of CKD and of the acute kidney injury to CKD transi- These include inflammation, an altered endothelial-tubular epi- tion [10, 11]. Both acute and chronic kidney diseases result in thelial cell crosstalk, a relative deficiency in angiogenic growth capillary rarefaction in preclinical models and humans. Thus, factors, loss of pericytes, increased activity of TGF-b1 and unilateral ureteral obstruction [12], remnant kidney model [13], thrombospondin-1, vitamin D deficiency, a link to lymphatic chronic allograft rejection [14] Col4a3-deficiency [15] and glo- neoangiogenesis and INK4a/ARF (Cylin-dependent kinase inhib- merulonephritis [16] are characterized by peritubular capillary itor 2a; CDKN2A). loss associated with interstitial fibrosis and tubular atrophy. Although the sequence of events connecting peritubular capil- lary loss to fibrosis and tubular atrophy is still not completely Inflammation and crosstalk between tubular characterized, hypoxia due to peritubular capillary rarefaction epithelial cells and capillary endothelial cells is thought to be a primary event in CKD and peritubular capil- lary rarefaction has been associated with reduced kidney regen- There is a bidirectional relationship between tubular epithelial erative capacity [17]. The functional micro-CT findings of cells and capillary endothelial cells. Primary tubular epithelial Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Capillary rarefaction and kidney | 297 Hypoxia resulting from peritubular capillary rarefaction pro- motes Hypoxia inducible factor (HIF) activation and the expres- sion of HIF-dependent genes such as VEGF, potentially favoring new capillary formation and thus offsetting capillary rarefac- tion [27, 35]. Thus, VEGF release could be considered a compen- satory response that enhances peritubular capillary density [36]. Indeed, kidney-derived mesenchymal stem cells (MSCs) reduce peritubular capillary rarefaction via secretion of VEGF [37] and cobalt-induced HIF activation mitigated renal injury in a CKD model [38]. However, in the remnant kidney model in adriamycin-induced CKD in mice, and in human CKD, a sponta- neous increased HIF-1a expression was not associated with increased tubular cell VEGF, suggesting an HIF-VEGF blockade in chronically injured tubules [39, 40]. Indeed, loss of tubular VEGF resulted in substantial reduction of peritubular capillary density [7]. In this regard, a decreased renal expression of VEGF- A is associated with a reduction in peritubular capillary density in diabetic nephropathy [41]. The late stages of the remnant kid- ney model are also characterized by loss of VEGF expression and VEGF administration preserved peritubular capillaries and improved tubulointerstitial injury [13, 42]. In addition, as CKD progresses, shear stress in the peritubular capillary decreases, leading to lower nitric oxide and VEGF availability and facilitat- ing Fas-FasL-mediated endothelial cell apoptosis [27]. However, the biology of VEGF is complex and tightly regulated, since Fig. 1. Factors playing a role in capillary rarefaction. excess VEGF may also be deleterious. Excessive and uncon- trolled VEGF secretion may result in formation of leaky cell injury promotes capillary rarefaction [26] and capillary rare- and nonfunctional vessels, favoring inflammation, macrophage faction further promotes hypoxic tubular cell injury, thus creat- recruitment and fibrosis [36, 43]. Furthermore, the VEGF120 ing a vicious circle. and VEGF188 upregulated in preclinical CKD are dys-angiogenic There are several examples in which tubular injury precedes isoforms [44]. Thus, the role of VEGF isoforms may have differ- capillary rarefaction. Chronic ureteral obstruction results in tub- ent impact on capillary rarefaction. There are various isoforms ular atrophy, tubulointerstitial fibrosis and peritubular capillary of VEGF such as VEGF121, VEGF165, VEGF189 or VEGF206 [45]. rarefaction [12]. Exposure of proximal tubular cells to plasma However, although these isoforms have been known for a long proteins, as in proteinuric conditions, results in release of period, their specific impact on capillary rarefaction has not inflammatory cytokines from tubular cells, which may drive been studied widely. In one study it was shown that impaired capillary rarefaction [27]. Genetically modified mice have been adipose tissue angiogenesis is associated with overexpression used in conjunction with diphtheria toxin-induced sublethal of antiangiogenic isoform of VEGF-A165b [46]. As also suggested injury specific to proximal tubular cells, thus demonstrating above, recent evidence showed that VEGF164 is proangiogenic, that proximal tubular cell injury is sufficient to elicit a strong whereas VEGF120 and VEGF188 were dys-angiogenic [44]. peritubular inflammatory response with secondary interstitial Apparently, more studies are needed regarding VEGF isoforms fibrosis and peritubular capillary rarefaction [28]. and capillary rarefaction. Additionally, capillary rarefaction decreases tubular blood and oxygen supply, promoting the loss of tubular cell viability Loss of pericytes and tubular atrophy and interstitial fibrosis. Hypoxia causes oxidative stress [29, 30] and increased expression of lethal Specific ablation of pericytes using a genetic model resulted in inflammatory cytokines such as FasL, interleukin-1b and tumor endothelial cell damage within 10 days and subsequent perma- necrosis factor a (TNF-a)[30]. Inflammatory factors and cells nent peritubular capillary rarefaction [47]. An increase in the promote endothelial cell injury, including a pro-coagulant and distance between pericytes and endothelial cells, heralding pro-adhesive phenotype, leading to capillary occlusion by detachment of pericytes from capillaries, is an early feature of thrombosis, as well as to endothelial cell apoptosis. Impairment acute kidney injury [47]. Pericyte detachment and loss leads to of blood flow decreases laminar shear stress on endothelial structural instability of blood vessels and to capillary rarefac- cells, resulting in further endothelial apoptosis and tubular tion [48–50]. Furthermore, detached pericytes are key precursors hypoxia as a vicious circle [31]. This is especially striking in of myofibroblasts [51–53]. Pericytes-turned-myofibroblasts con- antibody-mediated rejection following kidney transplantation. tribute to interstitial fibrosis that leads to further capillary rare- During this type of rejection, endothelial cells become pro- faction [43]. Additionally, pericytes serve as a local stem cell thrombotic, causing platelet and leukocyte adhesion, which population that replenish differentiated interstitial and vascular eventually leads to increased cell death [32]. cells lost during aging [54]. The loss of this reparative capacity in the toxic renal microenvironment after acute kidney injury or during CKD progression promotes cellular death of the unstable VEGF endothelium, with subsequent capillary rarefaction [54, 55]. VEGF promotes peritubular capillary formation and prolifera- A number of mediators are involved in the crosstalk between tion [33, 34] and, as discussed above, anticancer drugs targeting endothelial cells and pericytes via discontinuities in the capil- VEGF signaling promote dermal capillary rarefaction [25]. lary basement membrane that helps maintain the normal Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 298 | B. Afsar et al. vessel structure and stability. platelet derived growth factor INK4a/ARF (CDKN2A) (PDGF)-b/PDGF receptor-beta (PDGFR-b) and angiopoietin-Tie2, Deletion of the INK4a/ARFlocus encoding p16 and p19 improved appear to be crucial for pericyte differentiation, recruitment and kidney regeneration and decreased capillary rarefaction after expansion during angiogenesis. Pericytes produce angiopoietin- renal ischemia-reperfusion [64]. p16 and p19 play a role in tubu- 1, a growth factor that stabilizes the microvasculature by acti- lar atrophy and interstitial fibrosis by promoting apoptosis and vating the endothelial Tie2 receptor. After renal injury cell senescence. endothelium-derived angiopoietin-2, an antagonist of angiopoietin-1, increases, favoring capillary leakiness and peri- cyte loss [56]. The endothelium and pericytes also communicate Potential implications for therapy and future via ephrinB2, TIMPs/matrix metalloproteinases and others [57]. research TGF-b, VEGF, Notch and Sphingosine-1-phosphate also regulate Since there is evidence that capillary rarefaction plays an blood vessel stability [55]. In addition, pericyte detachment and important role in CKD progression, tubular atrophy and intersti- myofibroblastic differentiation are associated with secretion of tial fibrosis and it contributes to the development of essential anti-angiogenic factors such as ADAMTS1 (a disintegrin and hypertension, prevention or treatment of capillary rarefaction metalloproteinase with thrombospondin motifs-1), which fur- may potentially halt the progression of CKD and hypertension. ther accelerate capillary regression induced by kallikrein [55]. The potential for intervention includes the use of already avail- Bearing these issues in mind one may think that replace- able drugs (e.g. specific antihypertensive agents) or novel thera- ment of stem cells and pericytes, in particular, may attenuate peutic approaches. renal injury. However, it may not always be the case. For exam- ple, Kim et al. showed that administration of autologous MSCs resulted in rapid aggravation of preexisting renal insufficiency. Antihypertensive medication Renal biopsy findings at dialysis showed severe interstitial fib- An unresolved issue is the distinct effect of different antihyper- rosis and inflammatory cell infiltration. This highlights the tensive medications on capillary rarefaction. Angiotensin-con- potential nephrotoxicity of autologous MSC therapy in CKD verting enzyme inhibitors and angiotensin-1 receptor blockers patients [58]. It was also concluded that regarding the results of may induce angiogenesis and reduce or even reverse microvas- the preliminary data about stem cell therapy, long-term follow- cular rarefaction [65]. In rats with CKD, an angiotensin II antago- up data are not available and there is an absence of consensus nist for 10 weeks regenerated the kidney vasculature that had between therapeutic protocols [59]. previously undergone rarefaction and this was associated with reduced apoptosis and increased endothelial cell proliferation TGF-b1 and thrombospondin-1 [66]. Angiotensin-converting enzyme inhibitors also decreased both peritubular capillary rarefaction and lymphatic neoangio- During hypoxia, TGF-b1 stimulates angiogenesis indirectly by genesisin a rat renal allograft model [63]. However, in observa- inducing VEGF-A expression [60]. However, TGF-b1 directly tional cross-sectional human studies, dermal capillary density causes endothelial cell apoptosis and capillary pruning and this in treated hypertensive individuals has been reported to be negative effect predominates during renal fibrosis [27]. lower than or higher than in control normotensive individuals Thrombospondin-1 could potentiate the fibrotic response [67, 68]. The reason for these seemingly contradictory findings by both activating TGF-b and exerting antiangiogenic actions, is unclear and may depend on the specific antihypertensive thus leading to capillary rarefaction [36]. Inhibition of thrombo- agents, length of untreated or treated hypertension, or other spondin expression suppressed tubulointerstitial fibrosis by factors. Only prospective studies are likely to provide significant promoting VEGF production and restoring peritubular capillary insights. density [61]. Vitamin D receptor activators (VDRA) Vitamin D deficiency The fact that vitamin D deficiency aggravates capillary rarefac- The role of vitamin D deficiency in tubulointerstitial damage tion does not necessarily imply that pharmacological vitamin D and peritubular capillary rarefaction following acute kidney doses of VDRA prevent kidney capillary rarefaction. We found injury induced by ischemia-reperfusion was studied in rats fed no report addressing this. However, in a randomized clinical vitamin D-free or standard diets for 35 days. On Day 28, rats trial, the VDRA paricalcitol slowed the progressive endothelial were randomized into four groups: control, vitamin D deficient, dysfunction of moderate CKD, pointing to potential endothelial bilateral kidney ischemia-reperfusion and a combination of preservation capabilities [69]. Moreover, calcitriol prevented both. Vitamin D deficiency alone led to reduced capillary den- reduction of cardiac capillary density in rats with CKD [70]. sity and it further exacerbated the capillary rarefaction induced by kidney ischemia-reperfusion [11]. Sirtuin 1 activators Link to lymphatic neoangiogenesis A number of sirtuin 1 activators are known, most notably resver- atrol, although the pharmacokinetic properties of resveratrol are Peritubular capillary rarefaction may be associated with simul- suboptimal and additional sirtuin 1 (SIRT1) activators have been taneous proliferation of lymphatic vessels. Cortex and medulla microvascular density was lower in end-stage renal allografts developed to delay aging and age-related diseases [71]. To our knowledge, these have not yet been tested for their preservation than in controls, while new lymphatic vessels were observed in the graft tubulointerstitium, but not in controls [62, 63]. The of kidney capillary density properties. However, sirtuin 1 may drivers of the divergent response of peritubular capillaries (rare- prevent capillary rarefaction. Sirtuin 1 is highly expressed in faction) and lymphatic capillaries (neoangiogenesis) should be endothelial cells and regulates angiogenesis signaling pathways explored in further studies, but there is some evidence for a role via its deacetylase activity [72]. In mice with inactive Sirtuin 1, of angiotensin II [63]. angiogenesis is compromised [73, 74]. Endothelial Sirtuin 1 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Capillary rarefaction and kidney | 299 dysfunction causes activation of endothelial Notch1 signaling, point to several potential therapeutic strategies. However, for which leads to enhanced apoptosis and senescence of peritubu- some mechanisms, it is still unclear whether the improvement lar capillary endothelial cells with impaired endothelial prolifera- in capillary rarefaction is a primary event, or an event secon- dary to the improvement in other factors such as tubular cell tion and expanded myofibroblast population, peritubular capillary rarefaction and fibrosis following kidney injury. injury or inflammation. Whether diminishing capillary rarefac- tion slows down the progression of CKD and the development Specifically, Sirtuin 1 mutant mice have more severe renal fibro- of hypertension remains to be defined in clinical trials. sis and renal function impairment than wild-type mice following induction of folic acid nephropathy [75]. Compared with wild- type kidneys, SIRT1 mutant kidneys up-regulate Delta-like 4 Funding (DLL4, a potent Notch1 ligand), Hey1 and Hes1 (Notch target A.O. was supported by Intensificacion ISCIII and RETIC genes) and Notch intracellular domain-1 (NICD1, active form of REDINREN RD 016/0009 FEDER funds. Notch1) in microvascular endothelial cells post-injury. SIRT1 mutant primary kidney microvascular endothelial cells display lower motility and vascular assembly, and faster senescence Conflict of interest statement than wild-type cells [10]. None declared. VEGF References Since VEGF is the major survival factor for capillary endothe- lium, it may attenuate capillary rarefaction. Administration of 1. Basile DP, Friedrich JL, Spahic J et al. Impaired endothelial recombinant VEGF-A121 decreased peritubular capillary rare- proliferation and mesenchymal transition contribute to vas- faction, improved renal function, lowered mortality and cular rarefaction following acute kidney injury. Am J Physiol reduced fibrosis in a remnant kidney model [13]. However, VEGF Renal Physiol 2011; 300: F721–F733 is not yet in clinical use, in part due to the potential for harm 2. Triantafyllou A, Anyfanti P, Pyrpasopoulou A et al. Capillary due to excess VEGF activity, which may depend on the tissue rarefaction as an index for the microvascular assessment of microenvironment and on the existence of two VEGF receptors, hypertensive patients. Curr Hypertens Rep 2015; 17: 33 VEGFR1, involved in the inflammatory responses, and VEGFR2, 3. Serne EH, Gans RO, ter Maaten JC et al. Impaired skin capil- predominantly mediating angiogenesis [72]. In this regard, a lary recruitment in essential hypertension is caused by both VEGF mutant with specificity for VEGFR2 resulted in increased functional and structural capillary rarefaction. Hypertension kidney damage, despite the supposed specificity for the VEGF 2001; 38: 238–242 receptor mediating the potentially beneficial effects [76]. A bet- 4. Ehling J, Babikova J, Gremse F et al. Quantitative micro- ter way to enhance VEGF activity and keep it within physiologi- computed tomography imaging of vascular dysfunction in progressive kidney diseases. J Am Soc Nephrol 2016; 27: cal levels may involve a family of HIF activators, the HIF prolyl hydroxylase inhibitors, to which are undergoing clinical trials to 520–532 5. von Stillfried S, Apitzsch JC, Ehling J et al. Contrast-enhanced treat anemia in patients with CKD [77]. These drugs increase CT imaging in patients with chronic kidney disease. hemoglobin levels without increasing blood pressure, an effect Angiogenesis 2016; 19: 525–535 ascribed to increased VEGF secretion. These agents should be 6. Herzlinger D, Hurtado R. Patterning the renal vascular bed. tested to prevent kidney capillary rarefaction. Semin Cell Dev Biol 2014; 36: 50–56 7. Dimke H, Sparks MA, Thomson BR et al. Tubulovascular cross- Stem cell therapy talk by vascular endothelial growth factor A maintains peri- Kidney-derived MSCs have also been suggested to ameliorate tubular microvasculature in kidney. J Am Soc Nephrol 2015; 26: capillary rarefaction through the release of proangiogenic fac- 1027–1038 tors, such as VEGF, or microparticles [78, 79]. Stem cell-derived 8. Safran M, Kim WY, O’Connell F et al. Mouse model for nonin- microparticles decrease endothelial-to-mesenchymal transi- vasive imaging of HIF prolyl hydroxylase activity: assess- tion, enhance endothelial cell proliferation and reduce apopto- ment of an oral agent that stimulates erythropoietin sis, resulting in decreased peritubular capillary rarefaction [78]. production. Proc Natl Acad Sci USA 2006; 103: 105–110 Microvesicles released from endothelial progenitor cells also 9. Inoue T, Kozawa E, Okada H et al. Noninvasive evaluation of protected against CKD progression by inhibiting capillary rare- kidney hypoxia and fibrosis using magnetic resonance imag- faction [80]. Injection of kidney progenitor-like cells into ani- ing. J Am Soc Nephrol 2011; 22: 1429–1434 mals with subtotal nephrectomy resulted in slower loss of renal 10. Kida Y, Zullo JA, Goligorsky MS. Endothelial sirtuin 1 inacti- function, and milder macrophage and myofibroblast recruit- vation enhances capillary rarefaction and fibrosis following ment, and vascular rarefaction [81]. Finally, adipose stromal kidney injury through Notch activation. Biochem Biophys Res cells accelerated recovery from renal ischemia-reperfusion, Commun 2016; 478: 1074–1079 decreasing inflammation and tubular injury, and preserving 11. de Braganca AC, Volpini RA, Mehrotra P et al. Vitamin D defi- peritubular capillaries [82]. The challenges for cell therapy are ciency contributes to vascular damage in sustained ischemic still enormous, but positive clinical trials have been reported in acute kidney injury. Physiol Rep 2016; 4; pii: 12829 recent, large-scale, Phase 3 trials in other fields of medicine [83]. 12. Ohashi R, Shimizu A, Masuda Y et al. Peritubular capillary regression during the progression of experimental obstruc- tive nephropathy. J Am Soc Nephrol 2002; 13: 1795–1805 Conclusion 13. Kang DH, Joly AH, Oh SW et al. Impaired angiogenesis in the In conclusion, capillary rarefaction contributes to the develop- remnant kidney model: I. Potential role of vascular endothe- ment and progression of CKD and, potentially, to hypertension. lial growth factor and thrombospondin-1. J Am Soc Nephrol Various mechanisms contribute to capillary rarefaction, which 2001; 12: 1434–1447 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 300 | B. Afsar et al. 34. Venkatachalam MA, Weinberg JM, Kriz W et al. Failed tubule 14. Ishii Y, Sawada T, Kubota K et al. Injury and progressive loss of peritubular capillaries in the development of chronic recovery, AKI-CKD transition, and kidney disease progres- allograft nephropathy. Kidney Int 2005; 67: 321–332 sion. J Am Soc Nephrol 2015; 26: 1765–1776 15. Ba ´b´ıckova ´ J, Klinkhammer BM, Buhl EM et al. Regardless of 35. Semenza GL. Hypoxia-inducible factors: mediators of cancer etiology, progressive renal disease causes ultrastructural progression and targets for cancer therapy. Trends Pharmacol and functional alterations of peritubular capillaries. Kidney Sci 2012; 33: 207–214 Int 2017; 91: 70–85 36. Gewin L, Zent R, Pozzi A. Progression of chronic kidney dis- 16. Ohashi R, Kitamura H, Yamanaka N. Peritubular capillary ease: too much cellular talk causes damage. Kidney Int 2017; injury during the progression of experimental glomerulo- 91: 552–560 nephritis in rats. J Am Soc Nephrol 2000; 11: 47–56 37. Ninichuk V, Gross O, Segerer S et al. Multipotent mesenchy- 17. Fine LG, Norman JT. Chronic hypoxia as a mechanism of mal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney diseases: from hypothesis to progression of chronic kidney disease in collagen4A3- novel therapeutics. Kidney Int 2008; 74: 867–872 deficient mice. Kidney Int 2006; 70: 121–129 38. Tanaka T, Kojima I, Ohse T et al. Cobalt promotes angiogene- 18. Pauletto P, Rattazzi M. Inflammation and hypertension: the search for a link. Nephrol Dial Transplant 2006; 21: 850–853 sis via hypoxia-inducible factor and protects tubulointersti- 19. Solak Y, Afsar B, Vaziri ND et al. Hypertension as an autoim- tium in the remnant kidney model. Lab Invest 2005; 85: mune and inflammatory disease. Hypertens Res 2016; 39: 1292–1307 567–573 39. Kairaitis LK, Wang Y, Gassmann M et al. HIF-1alpha expres- 20. Chen II, Prewitt RL, Dowell RF. Microvascular rarefaction in sion follows microvascular loss in advanced murine adria- spontaneously hypertensive rat cremaster muscle. Am J mycin nephrosis. Am J Physiol Renal Physiol 2005; 288: Physiol 1981; 241: H306–H310 F198–F206 21. Gasser P, Bu ¨ hler FR. Nailfold microcirculation in normoten- 40. Grone HJ, Simon M, Grone EF. Expression of vascular endo- sive and essential hypertensive subjects, as assessed by thelial growth factor in renal vascular disease and renal video-microscopy. J Hypertens 1992; 10: 83–86 allografts. J Pathol 1995; 177: 259–267 22. Triantafyllou A, Anyfanti P, Triantafyllou G et al. Impaired 41. Lindenmeyer MT, Kretzler M, Boucherot A et al. Interstitial metabolic profile is a predictor of capillary rarefaction in a vascular rarefaction and reduced VEGF-A expression in population of hypertensive and normotensive individuals. human diabetic nephropathy. J Am Soc Nephrol 2007; 18: J Am Soc Hypertens 2016; 10: 640–646 1765–1776 23. Ciuffetti G, Schillaci G, Innocente S et al. Capillary rarefaction 42. Schrijvers BF, Flyvbjerg A, Tilton RG et al. Pathophysiological and abnormal cardiovascular reactivity in hypertension. role of vascular endothelial growth factor in the remnant J Hypertens 2003; 21: 2297–2303 kidney. Nephron Exp Nephrol 2005; 101: e9–e15 24. Abdel-Qadir H, Ethier JL, Lee DS et al. Cardiovascular toxicity 43. Kawakami T, Mimura I, Shoji K et al. Hypoxia and fibrosis in of angiogenesis inhibitors in treatment of malignancy: a sys- chronic kidney disease: crossing at pericytes. Kidney Int Suppl tematic review and meta-analysis. Cancer Treat Rev 2017; 53: 2014; 4: 107–112 120–127 44. Lin S-L, Chang F-C, Schrimpf Cet al. Targeting endothelium- 25. van der Veldt AAM, de Boer MP, Boven E et al. Reduction in pericyte cross talk by inhibiting VEGF receptor signaling skin microvascular density and changes in vessel morphol- attenuates kidney microvascular rarefaction and fibrosis. ogy in patients treated with sunitinib. Anticancer Drugs 2010; Am J Pathol 2011; 178: 911–923 21: 439–446 45. Park JE, Keller GA, Ferrara N. The vascular endothelial 26. Bonventre JV. Can we target tubular damage to prevent renal growth factor (VEGF) isoforms: differential deposition into function decline in diabetes? Semin Nephrol 2012; 32: 452–462 the subepithelial extracellular matrix and bioactivity of 27. Ballermann BJ, Obeidat M. Tipping the balance from angio- extracellular matrix-bound VEGF. Mol Biol Cell 1993; 4: genesis to fibrosis in CKD. Kidney Int Suppl 2014; 4: 45–52 1317–1326 28. Grgic I, Campanholle G, Bijol V et al. Targeted proximal 46. Ngo DT, Farb MG, Kikuchi R et al. Antiangiogenic actions of tubule injury triggers interstitial fibrosis and glomeruloscle- vascular endothelial growth factor-A165b, an inhibitory iso- rosis. Kidney Int 2012; 82: 172–183 form of vascular endothelial growth factor-A, in human obe- 29. Choi YJ, Chakraborty S, Nguyen V. Peritubular capillary loss sity. Circulation 2014; 130: 1072–1080 is associated with chronic tubulointerstitial injury in human 47. Kramann R, Wongboonsin J, Chang-Panesso M et al. Gli1þ kidney: altered expression of vascular endothelial growth pericyte loss induces capillary rarefaction and proximal tub- factor. Hum Pathol 2000; 31: 1491–1497 ular injury. J Am Soc Nephrol 2017; 28: 776–784 30. Kida Y, Tchao BN, Yamaguchi I. Peritubular capillary rarefac- 48. Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte tion: a new therapeutic target in chronic kidney disease. interactions. Circ Res 2005; 97: 512–523 Pediatr Nephrol 2014; 29: 333–342 49. Franco M, Roswall P, Cortez E et al. Pericytes promote 31. Dimmeler S, Assmus B, Hermann C et al. Fluid shear stress endothelial cell survival through induction of autocrine stimulates phosphorylation of Akt in human endothelial VEGF-A signaling and Bcl-w expression. Blood 2011; 118: cells: involvement in suppression of apoptosis. Circ Res 1998; 2906–2917 83: 334–341 50. Tanaka T. A mechanistic link between renal ischemia and 32. Pober JS, Min W, Bradley JR. Mechanisms of endothelial dys- fibrosis. Med Mol Morphol 2017; 50: 1–8 function, injury, and death. Annu Rev Pathol 2009; 4: 71–95 51. Ninichuk V, Anders HJ. Bone marrow-derived progenitor 33. Hakroush S, Moeller MJ, Theilig F et al. Effects of increased cells and renal fibrosis. Front Biosci 2008; 13: 5163–5173 renal tubular vascular endothelial growth factor (VEGF) on 52. He J, Xu Y, Koya D et al. Role of the endothelial-to- fibrosis, cyst formation, and glomerular disease. Am J Pathol mesenchymal transition in renal fibrosis of chronic kidney 2009; 175: 1883–1895 disease. Clin Exp Nephrol 2013; 17: 488–497 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Capillary rarefaction and kidney | 301 chronic kidney disease: a randomized trial. Am J Nephrol 53. Duffield JS, Humphreys BD. Origin of new cells in the adult kidney: results from genetic labeling techniques. Kidney Int 2015; 42: 265–273 2011; 79: 494–501 70. Koleganova N, Piecha G, Ritz E et al. Calcitriol ameliorates 54. Kramann R, Humphreys BD. Kidney pericytes: roles in capillary deficit and fibrosis of the heart in subtotally neph- regeneration and fibrosis. Semin Nephrol 2014; 34: 374–383 rectomized rats. Nephrol Dial Transplant 2009; 24: 778–787 55. Fligny C, Duffield JS. Activation of pericytes: recent insights 71. Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for into kidney fibrosis and microvascular rarefaction. Curr Opin the treatment of aging and age-related diseases. Trends Rheumatol 2013; 25: 78–86 Pharmacol Sci 2014; 35: 146–154 56. Tsai Y-C, Chiu Y-W, Tsai J-C et al. Association of 72. Kida Y, Goligorsky MS. Sirtuins, cell senescence, and vascu- angiopoietin-2 with renal outcome in chronic kidney dis- lar aging. Can J Cardiol 2016; 32: 634–641 ease. PLoS One 2014; 9: e108862 73. Potente M, Ghaeni L, Baldessari D et al. SIRT1 controls endo- 57. Schrimpf C, Teebken OE, Wilhelmi M et al. The role of peri- thelial angiogenic functions during vascular growth. Genes cyte detachment in vascular rarefaction. J Vasc Res 2014; 51: Dev 2007; 21: 2644–2658 247–258 74. Guarani V, Deflorian G, Franco CA et al. Acetylation-depend- 58. Kim JS, Lee JH, Kwon O et al. Rapid deterioration of preexist- ent regulation of endothelial Notch signalling by the SIRT1 ing renal insufficiency after autologous mesenchymal stem deacetylase. Nature 2011; 473: 234–238 cell therapy. Kidney Res Clin Pract 2017; 36: 200–204 75. Vasko R, Xavier S, Chen J et al. Endothelial sirtuin 1 defi- 59. Peired AJ, Sisti A, Romagnani P. Mesenchymal stem cell- ciency perpetrates nephrosclerosis through downregulation based therapy for kidney disease: a review of clinical evi- of matrix metalloproteinase-14: relevance to fibrosis of vas- dence. Stem Cells Int 2016; 2016: 4798639 cular senescence. J Am Soc Nephrol 2014; 25: 276–291 60. Pertovaara L, Kaipainen A, Mustonen T. Vascular endothelial 76. Sato W, Tanabe K, Kosugi T et al. Selective stimulation of growth factor is induced in response to transforming growth VEGFR2 accelerates progressive renal disease. Am J Pathol factor-beta in fibroblastic and epithelial cells. J Biol Chem 2011; 179: 155–166 1994; 269: 6271–6274 77. Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxy- 61. Sun D, Ma Y, Han H et al. Thrombospondin-1 short hairpin lase inhibitors: a potential new treatment for anemia in RNA suppresses tubulointerstitial fibrosis in the kidney of patients with CKD. Am J Kidney Dis 2017; 69: 815–826 ureteral obstruction by ameliorating peritubular capillary 78. Choi HY, Lee HG, Kim BS et al. Mesenchymal stem injury. Kidney Blood Press Res 2012; 35: 35–47 cell-derived microparticles ameliorate peritubular capillary 62. Adair A, Mitchell DR, Kipari T et al. Peritubular capillary rare- rarefaction via inhibition of endothelial-mesenchymal tran- faction and lymphangiogenesis in chronic allograft failure. sition and decrease tubulointerstitial fibrosis in unilateral Transplantation 2007; 83: 1542–1550 ureteral obstruction. Stem Cell Res Ther 2015; 6: 18 63. Hamar P, Kerjaschki D. Blood capillary rarefaction and lym- 79. Gatti S, Bruno S, Deregibus MC et al. Microvesicles derived phatic capillary neoangiogenesis are key contributors to from human adult mesenchymal stem cells protect against renal allograft fibrosis in an ACE inhibition rat model. Am J ischaemia-reperfusion-induced acute and chronic kidney Physiol Heart Circ Physiol 2016; 311: H981–H990 injury. Nephrol Dial Transplant 2011; 26: 1474–1483 64. Lee DH, Wolstein JM, Pudasaini B et al. INK4a deletion results 80. Cantaluppi V, Gatti S, Medica D et al. Microvesicles derived in improved kidney regeneration and decreased capillary from endothelial progenitor cells protect the kidney from rarefaction after ischemia-reperfusion injury. Am J Physiol ischemia-reperfusion injury by microRNA-dependent Renal Physiol 2012; 302: F183–F191 reprogramming of resident renal cells. Kidney Int 2012; 82: 65. Battegay EJ, de Miguel LS, Petrimpol M et al. Effects of anti- 412–427 hypertensive drugs on vessel rarefaction. Curr Opin 81. Chen CL, Chou KJ, Fang HC et al. Progenitor-like cells derived Pharmacol 2007; 7: 151–157 from mouse kidney protect against renal fibrosis in a rem- 66. Remuzzi A, Sangalli F, Macconi D et al. Regression of renal nant kidney model via decreased endothelial mesenchymal disease by angiotensin II antagonism is caused by regenera- transition. Stem Cell Res Ther 2015; 6: 239 tion of kidney vasculature. J Am Soc Nephrol 2016; 27: 699–705 82. Collett JA, Traktuev DO, Mehrotra P et al. Human adipose 67. Penna GLdeA, Garbero R, de F, Neves MF et al. Treatment of stromal cell therapy improves survival and reduces renal essential hypertension does not normalize capillary rarefac- inflammation and capillary rarefaction in acute kidney tion. Clinics 2008; 63: 613–618 68. Debbabi H, Uzan L, Mourad JJ et al. Increased skin capillary injury. J Cell Mol Med 2017; 21: 1420–1430 83. Pane ´s J, Garcı ´a-Olmo D, Van Assche G et al. Expanded alloge- density in treated essential hypertensive patients. Am J neic adipose-derived mesenchymal stem cells (Cx601) for com- Hypertens 2006; 19: 477–483 69. Lundwall K, Jo ¨ rneskog G, Jacobson SH et al. Paricalcitol, plex perianal fistulas in Crohn’s disease: a phase 3 randomised, microvascular and endothelial function in non-diabetic double-blind controlled trial. Lancet 2016; 388: 1281–1290 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Capillary rarefaction from the kidney point of view

Free
7 pages

Loading next page...
 
/lp/ou_press/capillary-rarefaction-from-the-kidney-point-of-view-KQsZKQJA60
Publisher
Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
ISSN
2048-8505
eISSN
2048-8513
D.O.I.
10.1093/ckj/sfx133
Publisher site
See Article on Publisher Site

Abstract

Capillary rarefaction is broadly defined as a reduction in vascular density. Capillary rarefaction in the kidneys is thought to promote hypoxia, impair hemodynamic responses and predispose to chronic kidney disease (CKD) progression and hypertension development. Various mechanisms have been suggested to play a role in the development of capillary rarefaction, including inflammation, an altered endothelial-tubular epithelial cell crosstalk, a relative deficiency in angiogenic growth factors, loss of pericytes, increased activity of Transforming growth factor -b1 and thrombospondin-1, vitamin D deficiency, a link to lymphatic neoangiogenesis and INK4a/ARF (Cylin-dependent kinase inhibitor 2a; CDKN2A). In this review, we summarize the tools available to monitor capillary rarefaction noninvasively in the clinic, the contribution of capillary rarefaction to CKD and hypertension, the known mechanisms of capillary rarefaction, and potential future strategies to attenuate capillary rarefaction and reduce its negative impact. Therapeutic strategies to be explored in more detail include optimization of antihypertensive therapy, vitamin D receptor activators, sirtuin 1 activators, Hypoxia inducible factor prolyl hydroxylase inhibitors and stem cell therapy. Key words: capillary, chronic kidney disease, hypertension, hypoxia-inducible factor, pericyte, rarefaction thought to promote hypoxia, impair hemodynamic responses Introduction and potentially predispose to chronic kidney disease (CKD) pro- Emerging evidence suggests that the kidney has considerable gression and hypertension development [1]. In this review, we capacity to repair and regenerate. However, not all kidney cell summarize the tools available to monitor capillary rarefaction types have the same regenerative capacity. Unlike proximal noninvasively in the clinic, the role of capillary rarefaction in tubule cells, cells of the renal vasculature have a poor capacity the progression of CKD and the development of hypertension, for repair, which may lead to a persistent reduction in vascular the known mechanisms of capillary rarefaction, and potential density following an acute or chronic insult. The reduction in future strategies that attenuate capillary rarefaction and its vascular density is broadly termed ‘capillary rarefaction’ and is negative impact on CKD and hypertension. Received: July 11, 2017. Editorial decision: October 4, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 296 | B. Afsar et al. capillary rarefaction were observed before the onset of overt fib- Noninvasive in vivo assessment of capillary rosis and may be the earliest diagnostic and prognostic sign for rarefaction renal dysfunction. At histological level, CKD progression is asso- In kidney biopsy specimens, capillary rarefaction is assessed ciated with evidence of capillary injury, such as focal widening histologically. However, kidney biopsy is an invasive procedure, of the subendothelial space and higher numbers of endothelial not suitable for future clinical trials assessing the impact of vacuoles and caveolae, reduced numbers of endothelial fenes- therapeutic intervention on capillary rarefaction. Noninvasive trations and increased thickness of the cell soma and lamina quantitative analyses such as nailfold capillaroscopy a com- densa of the capillary basement membrane, and increased per- puted tomography (CT) are alternatives more suitable for meability [15]. repeated assessment in the clinic, the latter marred by radiation and contrast use, but allowing direct quantification of kidney Capillary rarefaction and hypertension vascular rarefaction. Dermal capillaries represent an ‘open’ and representative Capillary rarefaction has also been implicated in the pathogenesis window for the in vivo study of the human microcirculation that of essential hypertension. The pathogenesis of capillary can be directly, repetitively and easily visualized by noninvasive rarefaction in hypertension is unknown, but it may involve a low- techniques such as nailfold capillaroscopy to show capillary rar- grade inflammatory response [18, 19]. In spontaneously hyperten- efaction [2, 3]. However, visual inspection of the capillaries is sive rats, there is rarefaction of arterioles and capillaries in skeletal limited by the depth of penetrance of light photons and pro- muscles [20]. Additionally, the number of nailfold capillaries is vides only a one-dimensional analysis of a three-dimensional lower in patients with untreated essential hypertension than in problem. controls [21]. In the non-renal population of hypertensive and nor- Functional in vivo micro-CT imaging has allowed accurate motensive individuals, capillary density significantly correlated assessment of vessel dysfunction in preclinical CKD [4]. with high-density lipoprotein/low-density lipoprotein ratio, but Furthermore, small-caliber artery rarefaction (interlobular not with serum vascular endothelial growth factor (VEGF) or with artery and more distal branches) can be followed separately high-sensitivity C-reactive protein. An inverse association was from capillary rarefaction [4]. In humans, contrast-enhanced CT found with body mass index, insulin levels and homeostasis angiography has also been used to assess kidney vascular rare- model assessment-insulin resistance [22]. faction by quantifying renal blood volume. Renal blood volume In essential hypertension, capillary rarefaction was associated was lower in the cortex of CKD patients than in controls and with cardiovascular reactivity and exercise-induced rheological closely mirrored capillary rarefaction in the corresponding abnormalities. In all, 61 men with essential hypertension and nephrectomy specimens. In patients with follow-up CT angiog- capillary rarefaction (<80 capillaries per field), and 20 age- and raphy, reduction of renal function was paralleled by a decline in sex-matched controls underwent a strenuous cycle ergometer renal blood volume [5]. test to monitor, during exercise and recovery, the blood pressure profile, the hemorheological pattern and other parameters. Capillary rarefaction and CKD progression Hypertensive men with <72 capillaries per field had an abnormal hemorheological profile before exercise. The physiological The major branches of the renal artery conduct more than 90% response to exercise was observed only in controls and in hyper- of renal blood flow directly to the glomerular capillary bed tensives with >73 capillaries per field. Abnormal responses to located in the kidney cortex [6]. Then, the efferent arteriole exercise worsened as capillaries were more rarefied [23]. branches into peritubular capillaries, which initially supply oxy- Finally, hypertension is a frequent side effect of anti- gen and nutrients to the highly metabolically active proximal angiogenesis therapy targeting VEGF receptor signaling in can- tubular cells. Less than 10% of the arterial blood flow is deliv- cer patients, to the point that development of hypertension ered to the medulla and then to more profound parts of the implies adequate VEGF inhibition and is associated with nephron. As a result, the cortex pO is between 30 and 50 improved tumor responses [24]. In this regard, the receptor tyro- mmHg, while in the medulla and medullary rays it is 10–20 sine kinase sunitinib promoted dermal capillary rarefaction and mmHg, the lowest in the body [7, 8]. Thus, even under physio- this could be one of the mechanisms for hypertension develop- logical circumstances, tubular cells, especially in some parts of ment in these patients [25]. the nephron, are relatively hypoxic. It is meaningful that erythropoietin-producing cells reside in the kidney, where they can sensitively detect hypoxia due to anemia. Under pathologi- Mechanisms of capillary rarefaction cal circumstances, the hypoxic areas may extend even into cor- Recent evidence has identified various mechanisms that con- tex region [9]. In this regard, peritubular capillary rarefaction is tribute to the development of capillary rarefaction (Figure 1). a hallmark of CKD and of the acute kidney injury to CKD transi- These include inflammation, an altered endothelial-tubular epi- tion [10, 11]. Both acute and chronic kidney diseases result in thelial cell crosstalk, a relative deficiency in angiogenic growth capillary rarefaction in preclinical models and humans. Thus, factors, loss of pericytes, increased activity of TGF-b1 and unilateral ureteral obstruction [12], remnant kidney model [13], thrombospondin-1, vitamin D deficiency, a link to lymphatic chronic allograft rejection [14] Col4a3-deficiency [15] and glo- neoangiogenesis and INK4a/ARF (Cylin-dependent kinase inhib- merulonephritis [16] are characterized by peritubular capillary itor 2a; CDKN2A). loss associated with interstitial fibrosis and tubular atrophy. Although the sequence of events connecting peritubular capil- lary loss to fibrosis and tubular atrophy is still not completely Inflammation and crosstalk between tubular characterized, hypoxia due to peritubular capillary rarefaction epithelial cells and capillary endothelial cells is thought to be a primary event in CKD and peritubular capil- lary rarefaction has been associated with reduced kidney regen- There is a bidirectional relationship between tubular epithelial erative capacity [17]. The functional micro-CT findings of cells and capillary endothelial cells. Primary tubular epithelial Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Capillary rarefaction and kidney | 297 Hypoxia resulting from peritubular capillary rarefaction pro- motes Hypoxia inducible factor (HIF) activation and the expres- sion of HIF-dependent genes such as VEGF, potentially favoring new capillary formation and thus offsetting capillary rarefac- tion [27, 35]. Thus, VEGF release could be considered a compen- satory response that enhances peritubular capillary density [36]. Indeed, kidney-derived mesenchymal stem cells (MSCs) reduce peritubular capillary rarefaction via secretion of VEGF [37] and cobalt-induced HIF activation mitigated renal injury in a CKD model [38]. However, in the remnant kidney model in adriamycin-induced CKD in mice, and in human CKD, a sponta- neous increased HIF-1a expression was not associated with increased tubular cell VEGF, suggesting an HIF-VEGF blockade in chronically injured tubules [39, 40]. Indeed, loss of tubular VEGF resulted in substantial reduction of peritubular capillary density [7]. In this regard, a decreased renal expression of VEGF- A is associated with a reduction in peritubular capillary density in diabetic nephropathy [41]. The late stages of the remnant kid- ney model are also characterized by loss of VEGF expression and VEGF administration preserved peritubular capillaries and improved tubulointerstitial injury [13, 42]. In addition, as CKD progresses, shear stress in the peritubular capillary decreases, leading to lower nitric oxide and VEGF availability and facilitat- ing Fas-FasL-mediated endothelial cell apoptosis [27]. However, the biology of VEGF is complex and tightly regulated, since Fig. 1. Factors playing a role in capillary rarefaction. excess VEGF may also be deleterious. Excessive and uncon- trolled VEGF secretion may result in formation of leaky cell injury promotes capillary rarefaction [26] and capillary rare- and nonfunctional vessels, favoring inflammation, macrophage faction further promotes hypoxic tubular cell injury, thus creat- recruitment and fibrosis [36, 43]. Furthermore, the VEGF120 ing a vicious circle. and VEGF188 upregulated in preclinical CKD are dys-angiogenic There are several examples in which tubular injury precedes isoforms [44]. Thus, the role of VEGF isoforms may have differ- capillary rarefaction. Chronic ureteral obstruction results in tub- ent impact on capillary rarefaction. There are various isoforms ular atrophy, tubulointerstitial fibrosis and peritubular capillary of VEGF such as VEGF121, VEGF165, VEGF189 or VEGF206 [45]. rarefaction [12]. Exposure of proximal tubular cells to plasma However, although these isoforms have been known for a long proteins, as in proteinuric conditions, results in release of period, their specific impact on capillary rarefaction has not inflammatory cytokines from tubular cells, which may drive been studied widely. In one study it was shown that impaired capillary rarefaction [27]. Genetically modified mice have been adipose tissue angiogenesis is associated with overexpression used in conjunction with diphtheria toxin-induced sublethal of antiangiogenic isoform of VEGF-A165b [46]. As also suggested injury specific to proximal tubular cells, thus demonstrating above, recent evidence showed that VEGF164 is proangiogenic, that proximal tubular cell injury is sufficient to elicit a strong whereas VEGF120 and VEGF188 were dys-angiogenic [44]. peritubular inflammatory response with secondary interstitial Apparently, more studies are needed regarding VEGF isoforms fibrosis and peritubular capillary rarefaction [28]. and capillary rarefaction. Additionally, capillary rarefaction decreases tubular blood and oxygen supply, promoting the loss of tubular cell viability Loss of pericytes and tubular atrophy and interstitial fibrosis. Hypoxia causes oxidative stress [29, 30] and increased expression of lethal Specific ablation of pericytes using a genetic model resulted in inflammatory cytokines such as FasL, interleukin-1b and tumor endothelial cell damage within 10 days and subsequent perma- necrosis factor a (TNF-a)[30]. Inflammatory factors and cells nent peritubular capillary rarefaction [47]. An increase in the promote endothelial cell injury, including a pro-coagulant and distance between pericytes and endothelial cells, heralding pro-adhesive phenotype, leading to capillary occlusion by detachment of pericytes from capillaries, is an early feature of thrombosis, as well as to endothelial cell apoptosis. Impairment acute kidney injury [47]. Pericyte detachment and loss leads to of blood flow decreases laminar shear stress on endothelial structural instability of blood vessels and to capillary rarefac- cells, resulting in further endothelial apoptosis and tubular tion [48–50]. Furthermore, detached pericytes are key precursors hypoxia as a vicious circle [31]. This is especially striking in of myofibroblasts [51–53]. Pericytes-turned-myofibroblasts con- antibody-mediated rejection following kidney transplantation. tribute to interstitial fibrosis that leads to further capillary rare- During this type of rejection, endothelial cells become pro- faction [43]. Additionally, pericytes serve as a local stem cell thrombotic, causing platelet and leukocyte adhesion, which population that replenish differentiated interstitial and vascular eventually leads to increased cell death [32]. cells lost during aging [54]. The loss of this reparative capacity in the toxic renal microenvironment after acute kidney injury or during CKD progression promotes cellular death of the unstable VEGF endothelium, with subsequent capillary rarefaction [54, 55]. VEGF promotes peritubular capillary formation and prolifera- A number of mediators are involved in the crosstalk between tion [33, 34] and, as discussed above, anticancer drugs targeting endothelial cells and pericytes via discontinuities in the capil- VEGF signaling promote dermal capillary rarefaction [25]. lary basement membrane that helps maintain the normal Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 298 | B. Afsar et al. vessel structure and stability. platelet derived growth factor INK4a/ARF (CDKN2A) (PDGF)-b/PDGF receptor-beta (PDGFR-b) and angiopoietin-Tie2, Deletion of the INK4a/ARFlocus encoding p16 and p19 improved appear to be crucial for pericyte differentiation, recruitment and kidney regeneration and decreased capillary rarefaction after expansion during angiogenesis. Pericytes produce angiopoietin- renal ischemia-reperfusion [64]. p16 and p19 play a role in tubu- 1, a growth factor that stabilizes the microvasculature by acti- lar atrophy and interstitial fibrosis by promoting apoptosis and vating the endothelial Tie2 receptor. After renal injury cell senescence. endothelium-derived angiopoietin-2, an antagonist of angiopoietin-1, increases, favoring capillary leakiness and peri- cyte loss [56]. The endothelium and pericytes also communicate Potential implications for therapy and future via ephrinB2, TIMPs/matrix metalloproteinases and others [57]. research TGF-b, VEGF, Notch and Sphingosine-1-phosphate also regulate Since there is evidence that capillary rarefaction plays an blood vessel stability [55]. In addition, pericyte detachment and important role in CKD progression, tubular atrophy and intersti- myofibroblastic differentiation are associated with secretion of tial fibrosis and it contributes to the development of essential anti-angiogenic factors such as ADAMTS1 (a disintegrin and hypertension, prevention or treatment of capillary rarefaction metalloproteinase with thrombospondin motifs-1), which fur- may potentially halt the progression of CKD and hypertension. ther accelerate capillary regression induced by kallikrein [55]. The potential for intervention includes the use of already avail- Bearing these issues in mind one may think that replace- able drugs (e.g. specific antihypertensive agents) or novel thera- ment of stem cells and pericytes, in particular, may attenuate peutic approaches. renal injury. However, it may not always be the case. For exam- ple, Kim et al. showed that administration of autologous MSCs resulted in rapid aggravation of preexisting renal insufficiency. Antihypertensive medication Renal biopsy findings at dialysis showed severe interstitial fib- An unresolved issue is the distinct effect of different antihyper- rosis and inflammatory cell infiltration. This highlights the tensive medications on capillary rarefaction. Angiotensin-con- potential nephrotoxicity of autologous MSC therapy in CKD verting enzyme inhibitors and angiotensin-1 receptor blockers patients [58]. It was also concluded that regarding the results of may induce angiogenesis and reduce or even reverse microvas- the preliminary data about stem cell therapy, long-term follow- cular rarefaction [65]. In rats with CKD, an angiotensin II antago- up data are not available and there is an absence of consensus nist for 10 weeks regenerated the kidney vasculature that had between therapeutic protocols [59]. previously undergone rarefaction and this was associated with reduced apoptosis and increased endothelial cell proliferation TGF-b1 and thrombospondin-1 [66]. Angiotensin-converting enzyme inhibitors also decreased both peritubular capillary rarefaction and lymphatic neoangio- During hypoxia, TGF-b1 stimulates angiogenesis indirectly by genesisin a rat renal allograft model [63]. However, in observa- inducing VEGF-A expression [60]. However, TGF-b1 directly tional cross-sectional human studies, dermal capillary density causes endothelial cell apoptosis and capillary pruning and this in treated hypertensive individuals has been reported to be negative effect predominates during renal fibrosis [27]. lower than or higher than in control normotensive individuals Thrombospondin-1 could potentiate the fibrotic response [67, 68]. The reason for these seemingly contradictory findings by both activating TGF-b and exerting antiangiogenic actions, is unclear and may depend on the specific antihypertensive thus leading to capillary rarefaction [36]. Inhibition of thrombo- agents, length of untreated or treated hypertension, or other spondin expression suppressed tubulointerstitial fibrosis by factors. Only prospective studies are likely to provide significant promoting VEGF production and restoring peritubular capillary insights. density [61]. Vitamin D receptor activators (VDRA) Vitamin D deficiency The fact that vitamin D deficiency aggravates capillary rarefac- The role of vitamin D deficiency in tubulointerstitial damage tion does not necessarily imply that pharmacological vitamin D and peritubular capillary rarefaction following acute kidney doses of VDRA prevent kidney capillary rarefaction. We found injury induced by ischemia-reperfusion was studied in rats fed no report addressing this. However, in a randomized clinical vitamin D-free or standard diets for 35 days. On Day 28, rats trial, the VDRA paricalcitol slowed the progressive endothelial were randomized into four groups: control, vitamin D deficient, dysfunction of moderate CKD, pointing to potential endothelial bilateral kidney ischemia-reperfusion and a combination of preservation capabilities [69]. Moreover, calcitriol prevented both. Vitamin D deficiency alone led to reduced capillary den- reduction of cardiac capillary density in rats with CKD [70]. sity and it further exacerbated the capillary rarefaction induced by kidney ischemia-reperfusion [11]. Sirtuin 1 activators Link to lymphatic neoangiogenesis A number of sirtuin 1 activators are known, most notably resver- atrol, although the pharmacokinetic properties of resveratrol are Peritubular capillary rarefaction may be associated with simul- suboptimal and additional sirtuin 1 (SIRT1) activators have been taneous proliferation of lymphatic vessels. Cortex and medulla microvascular density was lower in end-stage renal allografts developed to delay aging and age-related diseases [71]. To our knowledge, these have not yet been tested for their preservation than in controls, while new lymphatic vessels were observed in the graft tubulointerstitium, but not in controls [62, 63]. The of kidney capillary density properties. However, sirtuin 1 may drivers of the divergent response of peritubular capillaries (rare- prevent capillary rarefaction. Sirtuin 1 is highly expressed in faction) and lymphatic capillaries (neoangiogenesis) should be endothelial cells and regulates angiogenesis signaling pathways explored in further studies, but there is some evidence for a role via its deacetylase activity [72]. In mice with inactive Sirtuin 1, of angiotensin II [63]. angiogenesis is compromised [73, 74]. Endothelial Sirtuin 1 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Capillary rarefaction and kidney | 299 dysfunction causes activation of endothelial Notch1 signaling, point to several potential therapeutic strategies. However, for which leads to enhanced apoptosis and senescence of peritubu- some mechanisms, it is still unclear whether the improvement lar capillary endothelial cells with impaired endothelial prolifera- in capillary rarefaction is a primary event, or an event secon- dary to the improvement in other factors such as tubular cell tion and expanded myofibroblast population, peritubular capillary rarefaction and fibrosis following kidney injury. injury or inflammation. Whether diminishing capillary rarefac- tion slows down the progression of CKD and the development Specifically, Sirtuin 1 mutant mice have more severe renal fibro- of hypertension remains to be defined in clinical trials. sis and renal function impairment than wild-type mice following induction of folic acid nephropathy [75]. Compared with wild- type kidneys, SIRT1 mutant kidneys up-regulate Delta-like 4 Funding (DLL4, a potent Notch1 ligand), Hey1 and Hes1 (Notch target A.O. was supported by Intensificacion ISCIII and RETIC genes) and Notch intracellular domain-1 (NICD1, active form of REDINREN RD 016/0009 FEDER funds. Notch1) in microvascular endothelial cells post-injury. SIRT1 mutant primary kidney microvascular endothelial cells display lower motility and vascular assembly, and faster senescence Conflict of interest statement than wild-type cells [10]. None declared. VEGF References Since VEGF is the major survival factor for capillary endothe- lium, it may attenuate capillary rarefaction. Administration of 1. Basile DP, Friedrich JL, Spahic J et al. Impaired endothelial recombinant VEGF-A121 decreased peritubular capillary rare- proliferation and mesenchymal transition contribute to vas- faction, improved renal function, lowered mortality and cular rarefaction following acute kidney injury. Am J Physiol reduced fibrosis in a remnant kidney model [13]. However, VEGF Renal Physiol 2011; 300: F721–F733 is not yet in clinical use, in part due to the potential for harm 2. Triantafyllou A, Anyfanti P, Pyrpasopoulou A et al. Capillary due to excess VEGF activity, which may depend on the tissue rarefaction as an index for the microvascular assessment of microenvironment and on the existence of two VEGF receptors, hypertensive patients. Curr Hypertens Rep 2015; 17: 33 VEGFR1, involved in the inflammatory responses, and VEGFR2, 3. Serne EH, Gans RO, ter Maaten JC et al. Impaired skin capil- predominantly mediating angiogenesis [72]. In this regard, a lary recruitment in essential hypertension is caused by both VEGF mutant with specificity for VEGFR2 resulted in increased functional and structural capillary rarefaction. Hypertension kidney damage, despite the supposed specificity for the VEGF 2001; 38: 238–242 receptor mediating the potentially beneficial effects [76]. A bet- 4. Ehling J, Babikova J, Gremse F et al. Quantitative micro- ter way to enhance VEGF activity and keep it within physiologi- computed tomography imaging of vascular dysfunction in progressive kidney diseases. J Am Soc Nephrol 2016; 27: cal levels may involve a family of HIF activators, the HIF prolyl hydroxylase inhibitors, to which are undergoing clinical trials to 520–532 5. von Stillfried S, Apitzsch JC, Ehling J et al. Contrast-enhanced treat anemia in patients with CKD [77]. These drugs increase CT imaging in patients with chronic kidney disease. hemoglobin levels without increasing blood pressure, an effect Angiogenesis 2016; 19: 525–535 ascribed to increased VEGF secretion. These agents should be 6. Herzlinger D, Hurtado R. Patterning the renal vascular bed. tested to prevent kidney capillary rarefaction. Semin Cell Dev Biol 2014; 36: 50–56 7. Dimke H, Sparks MA, Thomson BR et al. Tubulovascular cross- Stem cell therapy talk by vascular endothelial growth factor A maintains peri- Kidney-derived MSCs have also been suggested to ameliorate tubular microvasculature in kidney. J Am Soc Nephrol 2015; 26: capillary rarefaction through the release of proangiogenic fac- 1027–1038 tors, such as VEGF, or microparticles [78, 79]. Stem cell-derived 8. Safran M, Kim WY, O’Connell F et al. Mouse model for nonin- microparticles decrease endothelial-to-mesenchymal transi- vasive imaging of HIF prolyl hydroxylase activity: assess- tion, enhance endothelial cell proliferation and reduce apopto- ment of an oral agent that stimulates erythropoietin sis, resulting in decreased peritubular capillary rarefaction [78]. production. Proc Natl Acad Sci USA 2006; 103: 105–110 Microvesicles released from endothelial progenitor cells also 9. Inoue T, Kozawa E, Okada H et al. Noninvasive evaluation of protected against CKD progression by inhibiting capillary rare- kidney hypoxia and fibrosis using magnetic resonance imag- faction [80]. Injection of kidney progenitor-like cells into ani- ing. J Am Soc Nephrol 2011; 22: 1429–1434 mals with subtotal nephrectomy resulted in slower loss of renal 10. Kida Y, Zullo JA, Goligorsky MS. Endothelial sirtuin 1 inacti- function, and milder macrophage and myofibroblast recruit- vation enhances capillary rarefaction and fibrosis following ment, and vascular rarefaction [81]. Finally, adipose stromal kidney injury through Notch activation. Biochem Biophys Res cells accelerated recovery from renal ischemia-reperfusion, Commun 2016; 478: 1074–1079 decreasing inflammation and tubular injury, and preserving 11. de Braganca AC, Volpini RA, Mehrotra P et al. Vitamin D defi- peritubular capillaries [82]. The challenges for cell therapy are ciency contributes to vascular damage in sustained ischemic still enormous, but positive clinical trials have been reported in acute kidney injury. Physiol Rep 2016; 4; pii: 12829 recent, large-scale, Phase 3 trials in other fields of medicine [83]. 12. Ohashi R, Shimizu A, Masuda Y et al. Peritubular capillary regression during the progression of experimental obstruc- tive nephropathy. J Am Soc Nephrol 2002; 13: 1795–1805 Conclusion 13. Kang DH, Joly AH, Oh SW et al. Impaired angiogenesis in the In conclusion, capillary rarefaction contributes to the develop- remnant kidney model: I. Potential role of vascular endothe- ment and progression of CKD and, potentially, to hypertension. lial growth factor and thrombospondin-1. J Am Soc Nephrol Various mechanisms contribute to capillary rarefaction, which 2001; 12: 1434–1447 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 300 | B. Afsar et al. 34. Venkatachalam MA, Weinberg JM, Kriz W et al. Failed tubule 14. Ishii Y, Sawada T, Kubota K et al. Injury and progressive loss of peritubular capillaries in the development of chronic recovery, AKI-CKD transition, and kidney disease progres- allograft nephropathy. Kidney Int 2005; 67: 321–332 sion. J Am Soc Nephrol 2015; 26: 1765–1776 15. Ba ´b´ıckova ´ J, Klinkhammer BM, Buhl EM et al. Regardless of 35. Semenza GL. Hypoxia-inducible factors: mediators of cancer etiology, progressive renal disease causes ultrastructural progression and targets for cancer therapy. Trends Pharmacol and functional alterations of peritubular capillaries. Kidney Sci 2012; 33: 207–214 Int 2017; 91: 70–85 36. Gewin L, Zent R, Pozzi A. Progression of chronic kidney dis- 16. Ohashi R, Kitamura H, Yamanaka N. Peritubular capillary ease: too much cellular talk causes damage. Kidney Int 2017; injury during the progression of experimental glomerulo- 91: 552–560 nephritis in rats. J Am Soc Nephrol 2000; 11: 47–56 37. Ninichuk V, Gross O, Segerer S et al. Multipotent mesenchy- 17. Fine LG, Norman JT. Chronic hypoxia as a mechanism of mal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney diseases: from hypothesis to progression of chronic kidney disease in collagen4A3- novel therapeutics. Kidney Int 2008; 74: 867–872 deficient mice. Kidney Int 2006; 70: 121–129 38. Tanaka T, Kojima I, Ohse T et al. Cobalt promotes angiogene- 18. Pauletto P, Rattazzi M. Inflammation and hypertension: the search for a link. Nephrol Dial Transplant 2006; 21: 850–853 sis via hypoxia-inducible factor and protects tubulointersti- 19. Solak Y, Afsar B, Vaziri ND et al. Hypertension as an autoim- tium in the remnant kidney model. Lab Invest 2005; 85: mune and inflammatory disease. Hypertens Res 2016; 39: 1292–1307 567–573 39. Kairaitis LK, Wang Y, Gassmann M et al. HIF-1alpha expres- 20. Chen II, Prewitt RL, Dowell RF. Microvascular rarefaction in sion follows microvascular loss in advanced murine adria- spontaneously hypertensive rat cremaster muscle. Am J mycin nephrosis. Am J Physiol Renal Physiol 2005; 288: Physiol 1981; 241: H306–H310 F198–F206 21. Gasser P, Bu ¨ hler FR. Nailfold microcirculation in normoten- 40. Grone HJ, Simon M, Grone EF. Expression of vascular endo- sive and essential hypertensive subjects, as assessed by thelial growth factor in renal vascular disease and renal video-microscopy. J Hypertens 1992; 10: 83–86 allografts. J Pathol 1995; 177: 259–267 22. Triantafyllou A, Anyfanti P, Triantafyllou G et al. Impaired 41. Lindenmeyer MT, Kretzler M, Boucherot A et al. Interstitial metabolic profile is a predictor of capillary rarefaction in a vascular rarefaction and reduced VEGF-A expression in population of hypertensive and normotensive individuals. human diabetic nephropathy. J Am Soc Nephrol 2007; 18: J Am Soc Hypertens 2016; 10: 640–646 1765–1776 23. Ciuffetti G, Schillaci G, Innocente S et al. Capillary rarefaction 42. Schrijvers BF, Flyvbjerg A, Tilton RG et al. Pathophysiological and abnormal cardiovascular reactivity in hypertension. role of vascular endothelial growth factor in the remnant J Hypertens 2003; 21: 2297–2303 kidney. Nephron Exp Nephrol 2005; 101: e9–e15 24. Abdel-Qadir H, Ethier JL, Lee DS et al. Cardiovascular toxicity 43. Kawakami T, Mimura I, Shoji K et al. Hypoxia and fibrosis in of angiogenesis inhibitors in treatment of malignancy: a sys- chronic kidney disease: crossing at pericytes. Kidney Int Suppl tematic review and meta-analysis. Cancer Treat Rev 2017; 53: 2014; 4: 107–112 120–127 44. Lin S-L, Chang F-C, Schrimpf Cet al. Targeting endothelium- 25. van der Veldt AAM, de Boer MP, Boven E et al. Reduction in pericyte cross talk by inhibiting VEGF receptor signaling skin microvascular density and changes in vessel morphol- attenuates kidney microvascular rarefaction and fibrosis. ogy in patients treated with sunitinib. Anticancer Drugs 2010; Am J Pathol 2011; 178: 911–923 21: 439–446 45. Park JE, Keller GA, Ferrara N. The vascular endothelial 26. Bonventre JV. Can we target tubular damage to prevent renal growth factor (VEGF) isoforms: differential deposition into function decline in diabetes? Semin Nephrol 2012; 32: 452–462 the subepithelial extracellular matrix and bioactivity of 27. Ballermann BJ, Obeidat M. Tipping the balance from angio- extracellular matrix-bound VEGF. Mol Biol Cell 1993; 4: genesis to fibrosis in CKD. Kidney Int Suppl 2014; 4: 45–52 1317–1326 28. Grgic I, Campanholle G, Bijol V et al. Targeted proximal 46. Ngo DT, Farb MG, Kikuchi R et al. Antiangiogenic actions of tubule injury triggers interstitial fibrosis and glomeruloscle- vascular endothelial growth factor-A165b, an inhibitory iso- rosis. Kidney Int 2012; 82: 172–183 form of vascular endothelial growth factor-A, in human obe- 29. Choi YJ, Chakraborty S, Nguyen V. Peritubular capillary loss sity. Circulation 2014; 130: 1072–1080 is associated with chronic tubulointerstitial injury in human 47. Kramann R, Wongboonsin J, Chang-Panesso M et al. Gli1þ kidney: altered expression of vascular endothelial growth pericyte loss induces capillary rarefaction and proximal tub- factor. Hum Pathol 2000; 31: 1491–1497 ular injury. J Am Soc Nephrol 2017; 28: 776–784 30. Kida Y, Tchao BN, Yamaguchi I. Peritubular capillary rarefac- 48. Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte tion: a new therapeutic target in chronic kidney disease. interactions. Circ Res 2005; 97: 512–523 Pediatr Nephrol 2014; 29: 333–342 49. Franco M, Roswall P, Cortez E et al. Pericytes promote 31. Dimmeler S, Assmus B, Hermann C et al. Fluid shear stress endothelial cell survival through induction of autocrine stimulates phosphorylation of Akt in human endothelial VEGF-A signaling and Bcl-w expression. Blood 2011; 118: cells: involvement in suppression of apoptosis. Circ Res 1998; 2906–2917 83: 334–341 50. Tanaka T. A mechanistic link between renal ischemia and 32. Pober JS, Min W, Bradley JR. Mechanisms of endothelial dys- fibrosis. Med Mol Morphol 2017; 50: 1–8 function, injury, and death. Annu Rev Pathol 2009; 4: 71–95 51. Ninichuk V, Anders HJ. Bone marrow-derived progenitor 33. Hakroush S, Moeller MJ, Theilig F et al. Effects of increased cells and renal fibrosis. Front Biosci 2008; 13: 5163–5173 renal tubular vascular endothelial growth factor (VEGF) on 52. He J, Xu Y, Koya D et al. Role of the endothelial-to- fibrosis, cyst formation, and glomerular disease. Am J Pathol mesenchymal transition in renal fibrosis of chronic kidney 2009; 175: 1883–1895 disease. Clin Exp Nephrol 2013; 17: 488–497 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Capillary rarefaction and kidney | 301 chronic kidney disease: a randomized trial. Am J Nephrol 53. Duffield JS, Humphreys BD. Origin of new cells in the adult kidney: results from genetic labeling techniques. Kidney Int 2015; 42: 265–273 2011; 79: 494–501 70. Koleganova N, Piecha G, Ritz E et al. Calcitriol ameliorates 54. Kramann R, Humphreys BD. Kidney pericytes: roles in capillary deficit and fibrosis of the heart in subtotally neph- regeneration and fibrosis. Semin Nephrol 2014; 34: 374–383 rectomized rats. Nephrol Dial Transplant 2009; 24: 778–787 55. Fligny C, Duffield JS. Activation of pericytes: recent insights 71. Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for into kidney fibrosis and microvascular rarefaction. Curr Opin the treatment of aging and age-related diseases. Trends Rheumatol 2013; 25: 78–86 Pharmacol Sci 2014; 35: 146–154 56. Tsai Y-C, Chiu Y-W, Tsai J-C et al. Association of 72. Kida Y, Goligorsky MS. Sirtuins, cell senescence, and vascu- angiopoietin-2 with renal outcome in chronic kidney dis- lar aging. Can J Cardiol 2016; 32: 634–641 ease. PLoS One 2014; 9: e108862 73. Potente M, Ghaeni L, Baldessari D et al. SIRT1 controls endo- 57. Schrimpf C, Teebken OE, Wilhelmi M et al. The role of peri- thelial angiogenic functions during vascular growth. Genes cyte detachment in vascular rarefaction. J Vasc Res 2014; 51: Dev 2007; 21: 2644–2658 247–258 74. Guarani V, Deflorian G, Franco CA et al. Acetylation-depend- 58. Kim JS, Lee JH, Kwon O et al. Rapid deterioration of preexist- ent regulation of endothelial Notch signalling by the SIRT1 ing renal insufficiency after autologous mesenchymal stem deacetylase. Nature 2011; 473: 234–238 cell therapy. Kidney Res Clin Pract 2017; 36: 200–204 75. Vasko R, Xavier S, Chen J et al. Endothelial sirtuin 1 defi- 59. Peired AJ, Sisti A, Romagnani P. Mesenchymal stem cell- ciency perpetrates nephrosclerosis through downregulation based therapy for kidney disease: a review of clinical evi- of matrix metalloproteinase-14: relevance to fibrosis of vas- dence. Stem Cells Int 2016; 2016: 4798639 cular senescence. J Am Soc Nephrol 2014; 25: 276–291 60. Pertovaara L, Kaipainen A, Mustonen T. Vascular endothelial 76. Sato W, Tanabe K, Kosugi T et al. Selective stimulation of growth factor is induced in response to transforming growth VEGFR2 accelerates progressive renal disease. Am J Pathol factor-beta in fibroblastic and epithelial cells. J Biol Chem 2011; 179: 155–166 1994; 269: 6271–6274 77. Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxy- 61. Sun D, Ma Y, Han H et al. Thrombospondin-1 short hairpin lase inhibitors: a potential new treatment for anemia in RNA suppresses tubulointerstitial fibrosis in the kidney of patients with CKD. Am J Kidney Dis 2017; 69: 815–826 ureteral obstruction by ameliorating peritubular capillary 78. Choi HY, Lee HG, Kim BS et al. Mesenchymal stem injury. Kidney Blood Press Res 2012; 35: 35–47 cell-derived microparticles ameliorate peritubular capillary 62. Adair A, Mitchell DR, Kipari T et al. Peritubular capillary rare- rarefaction via inhibition of endothelial-mesenchymal tran- faction and lymphangiogenesis in chronic allograft failure. sition and decrease tubulointerstitial fibrosis in unilateral Transplantation 2007; 83: 1542–1550 ureteral obstruction. Stem Cell Res Ther 2015; 6: 18 63. Hamar P, Kerjaschki D. Blood capillary rarefaction and lym- 79. Gatti S, Bruno S, Deregibus MC et al. Microvesicles derived phatic capillary neoangiogenesis are key contributors to from human adult mesenchymal stem cells protect against renal allograft fibrosis in an ACE inhibition rat model. Am J ischaemia-reperfusion-induced acute and chronic kidney Physiol Heart Circ Physiol 2016; 311: H981–H990 injury. Nephrol Dial Transplant 2011; 26: 1474–1483 64. Lee DH, Wolstein JM, Pudasaini B et al. INK4a deletion results 80. Cantaluppi V, Gatti S, Medica D et al. Microvesicles derived in improved kidney regeneration and decreased capillary from endothelial progenitor cells protect the kidney from rarefaction after ischemia-reperfusion injury. Am J Physiol ischemia-reperfusion injury by microRNA-dependent Renal Physiol 2012; 302: F183–F191 reprogramming of resident renal cells. Kidney Int 2012; 82: 65. Battegay EJ, de Miguel LS, Petrimpol M et al. Effects of anti- 412–427 hypertensive drugs on vessel rarefaction. Curr Opin 81. Chen CL, Chou KJ, Fang HC et al. Progenitor-like cells derived Pharmacol 2007; 7: 151–157 from mouse kidney protect against renal fibrosis in a rem- 66. Remuzzi A, Sangalli F, Macconi D et al. Regression of renal nant kidney model via decreased endothelial mesenchymal disease by angiotensin II antagonism is caused by regenera- transition. Stem Cell Res Ther 2015; 6: 239 tion of kidney vasculature. J Am Soc Nephrol 2016; 27: 699–705 82. Collett JA, Traktuev DO, Mehrotra P et al. Human adipose 67. Penna GLdeA, Garbero R, de F, Neves MF et al. Treatment of stromal cell therapy improves survival and reduces renal essential hypertension does not normalize capillary rarefac- inflammation and capillary rarefaction in acute kidney tion. Clinics 2008; 63: 613–618 68. Debbabi H, Uzan L, Mourad JJ et al. Increased skin capillary injury. J Cell Mol Med 2017; 21: 1420–1430 83. Pane ´s J, Garcı ´a-Olmo D, Van Assche G et al. Expanded alloge- density in treated essential hypertensive patients. Am J neic adipose-derived mesenchymal stem cells (Cx601) for com- Hypertens 2006; 19: 477–483 69. Lundwall K, Jo ¨ rneskog G, Jacobson SH et al. Paricalcitol, plex perianal fistulas in Crohn’s disease: a phase 3 randomised, microvascular and endothelial function in non-diabetic double-blind controlled trial. Lancet 2016; 388: 1281–1290 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018

Journal

Clinical Kidney JournalOxford University Press

Published: Nov 28, 2017

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off