Autophagy in proximal tubules protects against acute kidney injury

Man Jiang, Qingqing Wei, Guie Dong, Masaaki Komatsu, Yunchao Su, Zheng Dong

Research output: Contribution to journalArticle

260 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1271-1283
Number of pages13
JournalKidney International
Volume82
Issue number12
DOIs
StatePublished - Dec 2 2012

Keywords

  • Atg7
  • Ischemia-reperfusion
  • acute kidney injury
  • autophagy
  • cisplatin

ASJC Scopus subject areas

  • Nephrology

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