Rapamycin attenuates mitochondrial injury and renal tubular cell apoptosis in experimental contrast-induced acute kidney injury in rats

• Published in: Bioscience reports 2018-12, Vol.38 (6)
• Main Authors: Yang, Xueyan, Yan, Xiaojie, Yang, Dingping, Zhou, Junke, Song, Jie, Yang, Dingwei
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Animals; Apoptosis - drug effects; Contrast Media - adverse effects; Humans; Kidney - pathology; Kidney Tubules - drug effects; Kidney Tubules - pathology; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Mitochondria - pathology; Mitochondrial Degradation - drug effects; Oxidative Stress - drug effects; Rats; Reactive Oxygen Species - metabolism; Sirolimus - administration & dosage
• ISSN: 0144-8463; 1573-4935
• DOI: 10.1042/BSR20180876

Reactive oxygen species (ROS) overproduction and renal tubular epithelial cell (TEC) apoptosis are key mechanisms of contrast-induced acute kidney injury (CI-AKI). Mitochondria are the main source of intracellular ROS. In the present study, the characteristics of mitophagy and the effects of rapamycin on contrast-induced abnormalities in oxidative stress, mitochondrial injury and mitophagy, TEC apoptosis and renal function were investigated in a CI-AKI rat model. Rats were divided into control group, CI-AKI group, and pretreatment groups (with rapamycin dose of 2 or 5 mg/kg). CI-AKI was induced by intraperitoneal injection of iohexol (12.25 g iodine/kg). Renal malondialdehyde (MDA) and catalase (CAT) were measured as oxidative markers. Light-chain 3 (LC3), P62, Beclin-1, PTEN-induced putative kinase (Pink1), and cytochrome (Cyt ) expression were measured by Western blot. Mitochondrial membrane potential (ΔΨm) was determined by JC-1, colocalization of LC3-labeled autophagosomes with TOMM20-labeled mitochondria or LAMP2-labeled lysosomes was observed by fluorescence microscopy. Significantly increased serum creatinine (Scr), MDA and CAT, obvious mitochondrial injury including increase in cytosolic/mitochondrial Cyt and decrease in ΔΨm, TEC apoptosis were induced by contrast administration. Contrast administration induced an increased expression of LC3II/I, Beclin-1, and Pink1 and decreased expression of P62. Rapamycin pretreatment induced overexpression of LC3II/I and Beclin-1. Moreover, LC3-labeled autophagosomes increasingly overlapped with TOMM20-labeled mitochondria and LAMP2-labeled lysosomes in CI-AKI, which was further enhanced by rapamycin administration. Contrast-induced Scr increase, oxidative stress, mitochondrial injury, TEC apoptosis, and necrosis were dose-dependently attenuated by rapamycin pretreatment. Rapamycin exerts renoprotective effects against CI-AKI by attenuating mitochondrial injury and oxidative stress, which might be associated with increasing mitophagy.