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Archives of Toxicology (2018) 92:2245–2257
https://doi.org/10.1007/s00204-018-2225-9
ORGAN TOXICITY AND MECHANISMS
Comparison of iohexol and iodixanol induced nephrotoxicity,
mitochondrial damage and mitophagy in a new contrast-induced
acute kidney injury rat model
Wei Cheng
1
· Fei Zhao
1
· Cheng‑Yuan Tang
1
· Xu‑Wei Li
1
· Min Luo
1
· Shao‑Bin Duan
1
Received: 8 January 2018 / Accepted: 17 May 2018 / Published online: 2 June 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Recent progress in angiography and interventional therapy has revived interest in comparison of nephrotoxicity of low-or
iso-osmolar contrast media, but detailed mechanisms and effective treatments of contrast-induced acute kidney injury (CI-
AKI) remain elusive. We established a new model of CI-AKI and compared the nephrotoxicity of iohexol and iodixanol
with a focus on renal oxidative stress, mitochondrial damage and mitophagy. Our results showed that 48-h dehydration plus
furosemide injection before iohexol administration successfully induced CI-AKI in rats. Compared with iodixanol, iohexol
induced a greater decrease in renal function, more severe morphological damage and mitochondrial ultrastructural changes,
an increased number of apoptotic cells, decreased antioxidative enzymes with activation of NLRP3 inflammasome in renal
tissue. Renal contrast media kinetics showed the immediate excretion of iohexol and the transient renal accumulation of
iodixanol. Plasma mtDNA Tc numbers were positively correlated with markers of renal mitochondrial disruption but nega-
tively correlated with the level of serum creatinine and the score of tubular injury. Of note, iodixanol appeared to induce a
stronger activation of mitophagy than iohexol, evidenced by greater protein levels of LC3II and PINK1/Parkin in the renal
tissue of iodixanol-treated rats. Taken together, our results indicate that iohexol induced more severe nephrotoxicity than
iodixanol in vivo due to apoptosis, destruction of antioxidative defense machinery, activation of NLRP3 inflammasome,
mitochondrial damage and mitophagy. Plasma mtDNA may serve as a biological marker for renal mitochondrial disruption
and damage in CI-AKI. Antioxidative defense and mitophagy are involved in the process of CI-AKI and may be promising
targets of therapies.
Keywords Nephrotoxicity · Contrast media · Acute kidney injury · Oxidative stress · Mitochondrial damage · Mitophagy
Introduction
Contrast-induced acute kidney injury (CI-AKI) is defined
as the dynamic changes in serum creatinine (SCr) after
exposure to iodine contrast media (CM), and has become
the third leading cause of hospital-acquired acute kidney
injury (Silver et al. 2015). CI-AKI leads to prolonged
hospitalization and increased costs, and is a strong pre-
dictor of poor early and late outcomes (Centola et al. 2016;
Luo et al. 2017). Current guidelines recommend intrave-
nous hydration, use of low- (LOCM) or iso-osmolar con-
trast media (IOCM) and reduced volume of CM as preven-
tion strategies for CI-AKI (Wang et al. 2016). However,
detailed mechanisms and effective treatment of CI-AKI
remain elusive, and literature reports are controversial
of whether IOCM is associated with less risk for CI-AKI
than LOCM. Previous reports have proved the vital roles
of oxidative stress and inflammation in CI-AKI (Briguori
et al. 2011; Liu et al. 2014; Yang et al. 2015). Many stud-
ies have reported the protective role of autophagy and
mitophagy during renal ischemia/reperfusion (IRI) and
cisplatin induced AKI (Kaushal and Shah 2016; Tang et al.
2015). However, it remains unclear whether nephrotoxicity
of iohexol and iodixanol is associated with antioxidative
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0020 4-018-2225-9) contains
supplementary material, which is available to authorized users.
* Shao-Bin Duan
duansb528@csu.edu.cn
1
Department of Nephrology, The Second Xiangya
Hospital, Central South University, 139 Renmin Road,
Changsha 410011, Hunan, People’s Republic of China
@Phil_Robichaud
@deepthiw
@JoseServera