title: Autophagy in proximal tubules protects against acute kidney injury.
abstract: Autophagy is induced in renal tubular cells during acute kidney injury; however, whether this is protective or injurious remains controversial. We address this question by pharmacologic and genetic blockade of autophagy using mouse models of cisplatin- and ischemia-reperfusion-induced acute kidney injury. Chloroquine, a pharmacological inhibitor of autophagy, blocked autophagic flux and enhanced acute kidney injury in both models. Rapamycin, however, activated autophagy and protected against cisplatin-induced acute kidney injury. We also established a renal proximal tubule-specific autophagy-related gene 7-knockout mouse model shown to be defective in both basal and cisplatin-induced autophagy in kidneys. Compared with wild-type littermates, these knockout mice were markedly more sensitive to cisplatin-induced acute kidney injury as indicated by renal functional loss, tissue damage, and apoptosis. Mechanistically, these knockout mice had heightened activation of p53 and c-Jun N terminal kinase, the signaling pathways contributing to cisplatin acute kidney injury. Proximal tubular cells isolated from the knockout mice were more sensitive to cisplatin-induced apoptosis than cells from wild-type mice. In addition, the knockout mice were more sensitive to renal ischemia-reperfusion injury than their wild-type littermates. Thus, our results establish a renoprotective role of tubular cell autophagy in acute kidney injury where it may interfere with cell killing mechanisms.
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Health Sciences University and Charlie Norwood VA Medical Center, Augusta, Georgia 30912, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wei
authors.forename: Guie
authors.initials: G
authors.lastname: Dong
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Su
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D002945:Cisplatin; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D015427:Reperfusion Injury / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D015415:Biomarkers; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; D002738:Chloroquine; D003404:Creatinine; D048031:JNK Mitogen-Activated Protein Kinases; D000071193:Autophagy-Related Protein 7; D002945:Cisplatin; D020123:Sirolimus