Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signalsHernandez, Laura L.; Gregerson, Karen A.; Horseman, Nelson D.
doi: 10.1152/ajpendo.00666.2011pmid: 22318950
Breast cells drive bone demineralization during lactation and metastatic cancers. A shared mechanism among these physiological and pathological states is endocrine secretion of parathyroid hormone-related protein (PTHrP), which acts through osteoblasts to stimulate osteoclastic bone demineralization. The regulation of PTHrP has not been accounted for fully by any conventional mammotropic stimuli or tumor growth factors. Serotonin (5-HT) synthesis within breast epithelial cells is induced during lactation and in advancing breast cancer. Here we report that serotonin deficiency (knockout of tryptophan hydroxylase-1) results in a reduction of mammary PTHrP expression during lactation, which is rescued by restoring 5-HT synthesis. 5-HT induced PTHrP expression in lactogen-primed mammary epithelial cells from either mouse or cow. In human breast cancer cells 5-HT induced both PTHrP and the metastasis-associated transcription factor Runx2/Cbfa1. Based on receptor expression and pharmacological evidence, the 5-HT2 receptor type was implicated as being critical for induction of PTHrP and Runx2. These results connect 5-HT synthesis to the induction of bone-regulating factors in the normal mammary gland and in breast cancer cells. 5-hydroxytryptamine lactation osteoblast prolactin RANK ligand RUNX2/CBFA1 Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print February 7, 2012 , doi: 10.1152/ajpendo.00666.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E1009-E1015 » Abstract Free Full Text Free Full Text (PDF) Free All Versions of this Article: ajpendo.00666.2011v1 302/8/E1009 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Hernandez, L. L. Articles by Horseman, N. D. PubMed PubMed citation Articles by Hernandez, L. L. Articles by Horseman, N. D. Related Content Related Web Pages Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese miceKusakabe, Toru; Ebihara, Ken; Sakai, Takeru; Miyamoto, Licht; Aotani, Daisuke; Yamamoto, Yuji; Yamamoto-Kataoka, Sachiko; Aizawa-Abe, Megumi; Fujikura, Junji; Hosoda, Kiminori; Nakao, Kazuwa
doi: 10.1152/ajpendo.00198.2011pmid: 22275759
Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic β-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant diet-induced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Diet-induced obese (DIO) mice were infused with either saline (S), leptin (L; 500 μg·kg −1 ·day −1 ), amylin (A; 100 μg·kg −1 ·day −1 ), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pair-feeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPKα2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pair-feeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes. obesity diabetes adenosine 5′-monophosphate-activated protein kinase Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print January 24, 2012 , doi: 10.1152/ajpendo.00198.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E924-E931 » Abstract Free Full Text Full Text (PDF) All Versions of this Article: ajpendo.00198.2011v1 302/8/E924 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Kusakabe, T. Articles by Nakao, K. PubMed PubMed citation Articles by Kusakabe, T. Articles by Nakao, K. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytesVeilleux, Alain; Côté, Julie-Anne; Blouin, Karine; Nadeau, Mélanie; Pelletier, Mélissa; Marceau, Picard; Laberge, Philippe Y.; Luu-The, Van; Tchernof, André
doi: 10.1152/ajpendo.00069.2011pmid: 22275760
Adipogenesis and lipid storage in human adipose tissue are inhibited by androgens such as DHT. Inactivation of DHT to 3α-diol is stimulated by glucocorticoids in human preadipocytes. We sought to characterize glucocorticoid-induced androgen inactivation in human preadipocytes and to establish its role in the antiadipogenic action of DHT. Subcutaneous and omental primary preadipocyte cultures were established from fat samples obtained in subjects undergoing abdominal surgeries. Inactivation of DHT to 3α/β-diol for 24 h was measured in dexamethasone- or vehicle-treated cells. Specific downregulation of aldo-keto reductase 1C (AKR1C) enzymes in human preadipocytes was achieved using RNA interference. In whole adipose tissue sample, cortisol production was positively correlated with androgen inactivation in both subcutaneous and omental adipose tissue ( P < 0.05). Maximal dexamethasone (1 μM) stimulation of DHT inactivation was higher in omental compared with subcutaneous fat from men as well as subcutaneous and omental fat from women ( P < 0.05). A significant positive correlation was observed between BMI and maximal dexamethasone-induced DHT inactivation rates in subcutaneous and omental adipose tissue of men and women ( r = 0.24, n = 26, P < 0.01). siRNA-induced downregulation of AKR1C2, but not AKR1C1 or AKR1C3, significantly reduced basal and glucocorticoid-induced androgen inactivation rates ( P < 0.05). The inhibitory action of DHT on preadipocyte differentiation was potentiated following AKR1C2 but not AKR1C1 or AKR1C3 downregulation. Specifically, lipid accumulation, G3PDH activity, and FABP4 mRNA expression in differentiated preadipocytes exposed to DHT were reduced further upon AKR1C2 siRNA transfection. We conclude that glucocorticoid-induced androgen inactivation is mediated by AKR1C2 and is particularly effective in omental preadipocytes of obese men. The interplay between glucocorticoids and AKR1C2-dependent androgen inactivation may locally modulate adipogenesis and lipid accumulation in a depot-specific manner. 3α-hydroxysteroid dehydrogenase 5α-dihydrotestosterone dexamethasone Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print January 24, 2012 , doi: 10.1152/ajpendo.00069.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E941-E949 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00069.2011v1 302/8/E941 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Veilleux, A. Articles by Tchernof, A. PubMed PubMed citation Articles by Veilleux, A. Articles by Tchernof, A. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Signal transduction pathways in FSH regulation of rat Sertoli cell proliferationRiera, María F.; Regueira, Mariana; Galardo, María N.; Pellizzari, Eliana H.; Meroni, Silvina B.; Cigorraga, Selva B.
doi: 10.1152/ajpendo.00477.2011pmid: 22275758
The final number of Sertoli cells reached during the proliferative periods determines sperm production capacity in adulthood. It is well known that FSH is the major Sertoli cell mitogen; however, little is known about the signal transduction pathways that regulate the proliferation of Sertoli cells. The hypothesis of this investigation was that FSH regulates proliferation through a PI3K/Akt/mTORC1 pathway, and additionally, AMPK-dependent mechanisms counteract FSH proliferative effects. The present study was performed in 8-day-old rat Sertoli cell cultures. The results presented herein show that FSH, in addition to increasing p-Akt, p-mTOR, and p-p70S6K levels, increases p-PRAS40 levels, probably contributing to improving mTORC1 signaling. Furthermore, the decrease in FSH-stimulated p-Akt, p-mTOR, p-p70S6K, and p-PRAS40 levels in the presence of wortmannin emphasizes the participation of PI3K in FSH signaling. Additionally, the inhibition of FSH-stimulated Sertoli cell proliferation by the effect of wortmannin and rapamycin point to the relevance of the PI3K/Akt/mTORC1 signaling pathway in the mitotic activity of FSH. On the other hand, by activating AMPK, several interesting observations were made. Activation of AMPK produced an increase in Raptor phosphorylation, a decrease in p70S6K phosphorylation, and a decrease in FSH-stimulated Sertoli cell proliferation. The decrease in FSH-stimulated cell proliferation was accompanied by an increased expression of the cyclin-dependent kinase inhibitors (CDKIs) p19INK4d, p21Cip1, and p27Kip1. In summary, it is concluded that FSH regulates Sertoli cell proliferation with the participation of a PI3K/Akt/mTORC1 pathway and that AMPK activation may be involved in the detention of proliferation by, at least in part, a decrease in mTORC1 signaling and an increase in CDKI expression. follicle-stimulating hormone phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 adenosine 5′-monophosphate-activated protein kinase Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print January 24, 2012 , doi: 10.1152/ajpendo.00477.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E914-E923 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00477.2011v1 302/8/E914 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Riera, M. F. Articles by Cigorraga, S. B. PubMed PubMed citation Articles by Riera, M. F. Articles by Cigorraga, S. B. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Insulin stimulates fusion, but not tethering, of GLUT4 vesicles in skeletal muscle of HA-GLUT4-GFP transgenic miceLizunov, Vladimir A.; Stenkula, Karin G.; Lisinski, Ivonne; Gavrilova, Oksana; Yver, Dena R.; Chadt, Alexandra; Al-Hasani, Hadi; Zimmerberg, Joshua; Cushman, Samuel W.
doi: 10.1152/ajpendo.00466.2011pmid: 22297303
Insulin regulates glucose uptake into fat and muscle by modulating the subcellular distribution of GLUT4 between the cell surface and intracellular compartments. However, quantification of these translocation processes in muscle by classical subcellular fractionation techniques is confounded by contaminating microfibrillar protein; dynamic studies at the molecular level are almost impossible. In this study, we introduce a muscle-specific transgenic mouse model in which HA-GLUT4-GFP is expressed under the control of the MCK promoter. HA-GLUT4-GFP was found to translocate to the plasma membrane and T-tubules after insulin stimulation, thus mimicking endogenous GLUT4. To investigate the dynamics of GLUT4 trafficking in skeletal muscle, we quantified vesicles containing HA-GLUT4-GFP near the sarcolemma and T-tubules and analyzed insulin-stimulated exocytosis at the single vesicle level by total internal reflection fluorescence and confocal microscopy. We found that only 10% of the intracellular GLUT4 pool comprised mobile vesicles, whereas most of the GLUT4 structures remained stationary or tethered at the sarcolemma or T-tubules. In fact, most of the insulin-stimulated exocytosis emanated from pretethered vesicles, whereas the small pool of mobile GLUT4 vesicles was not significantly affected by insulin. Our data strongly suggest that the mobile pool of GLUT4 vesicles is not a major site of insulin action but rather locally distributed. Most likely, pretethered GLUT4 structures are responsible for the initial phase of insulin-stimulated exocytosis. hemagglutinin glucose transporter 4 green fluorescent protein insulin fusion « Previous | Next Article » Table of Contents This Article Published online before print January 31, 2012 , doi: 10.1152/ajpendo.00466.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E950-E960 » Abstract Free Full Text Free to you Full Text (PDF) Free to you Supplemental Videos All Versions of this Article: ajpendo.00466.2011v1 302/8/E950 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Lizunov, V. A. Articles by Cushman, S. W. PubMed PubMed citation Articles by Lizunov, V. A. Articles by Cushman, S. W. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Lack of myostatin alters intermyofibrillar mitochondria activity, unbalances redox status, and impairs tolerance to chronic repetitive contractions in musclePloquin, Claire; Chabi, Béatrice; Fouret, Gilles; Vernus, Barbara; Feillet-Coudray, Christine; Coudray, Charles; Bonnieu, Anne; Ramonatxo, Christelle
doi: 10.1152/ajpendo.00652.2011pmid: 22318951
Loss of myostatin (mstn) function leads to a decrease in mitochondrial content, a reduced expression of cytochrome c oxidase, and a lower citrate synthase activity in skeletal muscle. These data suggest functional or ultrastructural mitochondrial abnormalities that can impact on muscle endurance characteristics in such phenotype. To address this issue, we investigated subsarcolemmal and intermyofibrillar (IMF) mitochondrial activities, skeletal muscle redox homeostasis, and muscle fiber endurance quality in mstn-deficient mice (mstn knockout (KO)). We report that lack of mstn induced a decrease in the coupling of IMF mitochondria respiration, with significantly higher basal oxygen consumption. No lysis of mitochondrial cristae or excessive swelling were observed in mstn KO mice compared with wild-type (WT) mice. Concerning redox status, mstn KO gastrocnemius exhibited a significant decrease in lipid peroxidation levels (−56%; P < 0.01 vs. WT) together with a significant upregulation of the antioxidant glutathione system. In contrast, superoxide dismutase and catalase activities were altered in mstn KO, gastrocnemius and soleus with a reduction of up to 80% compared with WT animals. The force production observed after contractile endurance test was significantly lower in extensor digitorum longus and soleus muscles of mstn KO mice compared with the controls (17 ± 3 and 36 ± 5% vs. 28 ± 4 and 56 ± 5%, respectively, P < 0.05). Together, these findings indicate that, besides an increased skeletal muscle mass, genetic mstn inhibition has differential effects on redox homeostasis and mitochondrial function that would have functional consequences on muscle response to endurance exercise. skeletal muscle GDF-8 inactivation respiratory chain antioxidant contractile properties Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print February 7, 2012 , doi: 10.1152/ajpendo.00652.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E1000-E1008 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00652.2011v1 302/8/E1000 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Ploquin, C. Articles by Ramonatxo, C. PubMed PubMed citation Articles by Ploquin, C. Articles by Ramonatxo, C. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in micePamir, Nathalie; McMillen, Timothy S.; Edgel, Kimberly A.; Kim, Francis; LeBoeuf, Renée C.
doi: 10.1152/ajpendo.00447.2011pmid: 22318945
Lymphotoxin-α (LTα) is secreted by lymphocytes and acts through tumor necrosis factor-α receptors and the LTβ receptor. Our goals were to determine whether LT has a role in obesity and investigate whether LT contributes to the link between obesity and adipose tissue lymphocyte accumulation. LT deficient (LT −/− ) and wild-type (WT) mice were fed standard pelleted rodent chow or a high-fat/high-sucrose diet (HFHS) for 13 wk. Body weight, body composition, and food intake were measured. Glucose tolerance was assessed. Systemic and adipose tissue inflammatory statuses were evaluated by quantifying plasma adipokine levels and tissue macrophage and T cell-specific gene expression in abdominal fat. LT −/− mice were smaller (20%) and leaner (25%) than WT controls after 13 wk of HFHS diet feeding. LT −/− mice showed improved glucose tolerance, suggesting that, in WT mice, LT may impair glucose metabolism. Surprisingly, adipose tissue from rodent chow- and HFHS-fed LT −/− mice exhibited increased T lymphocyte and macrophage infiltration compared with WT mice. Despite the fact that LT −/− mice exhibited an enhanced inflammatory status at the systemic and tissue level even when fed rodent chow, they were protected from enhanced diet-induced obesity and insulin resistance. Thus, LT contributes to body weight and adiposity and is required to modulate the accumulation of immune cells in adipose tissue. macrophages lymphocytes cytokines diabetes Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print February 7, 2012 , doi: 10.1152/ajpendo.00447.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E961-E971 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00447.2011v1 302/8/E961 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Pamir, N. Articles by LeBoeuf, R. C. PubMed PubMed citation Articles by Pamir, N. Articles by LeBoeuf, R. C. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Fibroblast growth factor-23 abolishes 1,25-dihydroxyvitamin D3-enhanced duodenal calcium transport in male miceKhuituan, Pissared; Teerapornpuntakit, Jarinthorn; Wongdee, Kannikar; Suntornsaratoon, Panan; Konthapakdee, Nipaporn; Sangsaksri, Jintana; Sripong, Chanakarn; Krishnamra, Nateetip; Charoenphandhu, Narattaphol
doi: 10.1152/ajpendo.00620.2011pmid: 22275752
Despite being widely recognized as the important bone-derived phosphaturic hormone, whether fibroblast growth factor (FGF)-23 modulated intestinal calcium absorption remained elusive. Since FGF-23 could reduce the circulating level of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), FGF-23 probably compromised the 1,25(OH) 2 D 3 -induced intestinal calcium absorption. FGF-23 may also exert an inhibitory action directly through FGF receptors (FGFR) in the intestinal cells. Herein, we demonstrated by Ussing chamber technique that male mice administered 1 μg/kg 1,25(OH) 2 D 3 sc daily for 3 days exhibited increased duodenal calcium absorption, which was abolished by concurrent intravenous injection of recombinant mouse FGF-23. This FGF-23 administration had no effect on the background epithelial electrical properties, i.e., short-circuit current, transepithelial potential difference, and resistance. Immunohistochemical evidence of protein expressions of FGFR isoforms 1–4 in mouse duodenal epithelial cells suggested a possible direct effect of FGF-23 on the intestine. This was supported by the findings that FGF-23 directly added to the serosal compartment of the Ussing chamber and completely abolished the 1,25(OH) 2 D 3 -induced calcium absorption in the duodenal tissues taken from the 1,25(OH) 2 D 3 -treated mice. However, direct FGF-23 exposure did not decrease the duodenal calcium absorption without 1,25(OH) 2 D 3 preinjection. The observed FGF-23 action was mediated by MAPK/ERK, p38 MAPK, and PKC. Quantitative real-time PCR further showed that FGF-23 diminished the 1,25(OH) 2 D 3 -induced upregulation of TRPV5, TRPV6, and calbindin-D 9k , but not PMCA 1b expression in the duodenal epithelial cells. In conclusion, besides being a phosphatonin, FGF-23 was shown to be a novel calcium-regulating hormone that acted directly on the mouse intestine, thereby compromising the 1,25(OH) 2 D 3 -induced calcium absorption. calbindin-D 9k fibroblast growth factor receptor Klotho transient receptor potential vanilloid type 6 Ussing chamber Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print January 24, 2012 , doi: 10.1152/ajpendo.00620.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E903-E913 » Abstract Free Full Text Full Text (PDF) All Versions of this Article: ajpendo.00620.2011v1 302/8/E903 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Khuituan, P. Articles by Charoenphandhu, N. PubMed PubMed citation Articles by Khuituan, P. Articles by Charoenphandhu, N. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Mass spectrometry for the molecular imaging of angiotensin metabolism in kidneyGrobe, Nadja; Elased, Khalid M.; Cool, David R.; Morris, Mariana
doi: 10.1152/ajpendo.00515.2011pmid: 22318946
To better understand the tissue distribution and activity of enzymes involved in angiotensin II (Ang II) processing, we developed a novel molecular imaging method using matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. Mouse kidney sections (12 μm) were incubated with 10–1,000 μmol/l Ang II for 5–15 min at 37°C. The formed peptides Ang III and Ang-(1–7) were identified by MALDI-TOF/TOF. A third metabolite, Ang-(1–4), was generated from further degradation of Ang-(1–7). Enzymatic processing of Ang II was dose and time dependent and absent in heat-treated kidney sections. Distinct spatial distribution patterns (pseudocolor images) were observed for the peptides. Ang III was localized in renal medulla, whereas Ang-(1–7)/Ang-(1–4) was present in cortex. Regional specific peptide formation was confirmed using microdissected cortical and medullary biopsies. In vitro studies with recombinant enzymes confirmed activity of peptidases known to generate Ang III or Ang-(1–7) from Ang II: aminopeptidase A (APA), Ang-converting enzyme 2 (ACE2), prolyl carboxypeptidase (PCP), and prolyl endopeptidase (PEP). Renal medullary Ang III generation was blocked by APA inhibitor glutamate phosphonate. The ACE2 inhibitor MLN-4760 and PCP/PEP inhibitor Z-pro-prolinal reduced cortical Ang-(1–7) formation. Our results establish the power of MALDI imaging as a highly specific and information-rich analytical technique that will further aid our understanding of the role and site of Ang II processing in cardiovascular and renal pathologies. matrix-assisted laser desorption ionization imaging angiotensin-converting enzyme 2 prolyl carboxypeptidase prolyl endopeptidase aminopeptidase A Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print February 7, 2012 , doi: 10.1152/ajpendo.00515.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E1016-E1024 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00515.2011v1 302/8/E1016 most recent Classifications Innovative Methodology Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Grobe, N. Articles by Morris, M. PubMed PubMed citation Articles by Grobe, N. Articles by Morris, M. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555
Age-dependent renal cortical microvascular loss in female miceUrbieta-Caceres, Victor H.; Syed, Farhan A.; Lin, Jing; Zhu, Xiang-Yang; Jordan, Kyra L.; Bell, Caitlin C.; Bentley, Michael D.; Lerman, Amir; Khosla, Sundeep; Lerman, Lilach O.
doi: 10.1152/ajpendo.00411.2011pmid: 22318944
Renal function and blood flow decline during aging in association with a decrease in the number of intrarenal vessels, but if loss of estrogen contributes to this microvascular, rarefaction remains unclear. We tested the hypothesis that the decreased renal microvascular density with age is aggravated by loss of estrogen. Six-month-old female C57/BL6 mice underwent ovariectomy (Ovx) or sham operation and then were allowed to age to 18–22 mo. Another comparable group was replenished with estrogen after Ovx (Ovx+E), while a 6-mo-old group served as young controls. Kidneys were then dissected for evaluation of microvascular density (by micro-computed tomography) and angiogenic and fibrogenic factors. Cortical density of small microvessels (20–200 μm) was decreased in all aged groups compared with young controls (30.3 ± 5.8 vessels/mm 2 , P < 0.05), but tended to be lower in sham compared with Ovx and Ovx+E (9.9 ± 1.7 vs. 17.2 ± 4.2 and 18 ± 3.0 vessels/mm 2 , P = 0.08 and P = 0.02, respectively). Cortical density of larger microvessels (200–500 μm) decreased only in aged sham ( P = 0.04 vs. young control), and proangiogenic signaling was attenuated. On the other hand, renal fibrogenic mechanisms were aggravated in aged Ovx compared with aged sham, but blunted in Ovx+E, in association with downregulated transforming growth factor-β signaling and decreased oxidative stress in the kidney. Therefore, aging induced in female mice renal cortical microvascular loss, which was likely not mediated by loss of endogenous estrogen. However, estrogen may play a role in protecting the kidney by decreasing oxidative stress and attenuating mechanisms linked to renal interstitial fibrosis. kidney aging estrogen Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print February 7, 2012 , doi: 10.1152/ajpendo.00411.2011 AJP - Endo April 15, 2012 vol. 302 no. 8 E979-E986 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpendo.00411.2011v1 302/8/E979 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Urbieta-Caceres, V. H. Articles by Lerman, L. O. PubMed PubMed citation Articles by Urbieta-Caceres, V. H. Articles by Lerman, L. O. Related Content Load related web page information Current Content Alert me to new issues of AJP - Endo About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1849 Online ISSN: 1522-1555