Autophagy in proximal tubules protects against acute kidney injury

Kidney Int. 2012 Dec;82(12):1271-83. doi: 10.1038/ki.2012.261. Epub 2012 Aug 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Kidney Injury / blood
  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Apoptosis
  • Autophagy* / drug effects
  • Autophagy-Related Protein 7
  • Biomarkers / blood
  • Blood Urea Nitrogen
  • Cells, Cultured
  • Chloroquine / pharmacology
  • Cisplatin
  • Creatinine / blood
  • Cytoprotection
  • Disease Models, Animal
  • Enzyme Activation
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / genetics
  • Reperfusion Injury / blood
  • Reperfusion Injury / chemically induced
  • Reperfusion Injury / genetics
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Signal Transduction
  • Sirolimus / pharmacology
  • Time Factors
  • Tumor Suppressor Protein p53 / metabolism


  • Atg7 protein, mouse
  • Biomarkers
  • Microtubule-Associated Proteins
  • Tumor Suppressor Protein p53
  • Chloroquine
  • Creatinine
  • JNK Mitogen-Activated Protein Kinases
  • Autophagy-Related Protein 7
  • Cisplatin
  • Sirolimus