Survivin mediates renal proximal tubule recovery from AKI

Jianchun Chen, Jiankang Chen, Edward M. Conway, Raymond C. Harris

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

AKI induces the renoprotective upregulation of survivin expression in kidney epithelial cells, but the underlyingmechanisms have not been identified. To determine the role of survivin in renal recovery from AKI, we generated mice with renal proximal tubule-specific deletion of survivin (survivinptKO). Renal survivin expression increased substantially in response to ischemia-reperfusion (I/R) injury in control littermates but remained minimal in survivinptKO mice. Functional and histologic data indicated similar degrees of renal injury in survivinptKO and control mice 24 hours after reperfusion, but recovery was markedly delayed in survivinptKO mice. In MCT cells, a mouse renal proximal tubule cell line, ATP depletion by antimycin A treatment upregulated survivin expression through a phospho-STAT3-dependent pathway. In wild-type mice, inhibition of STAT3 kinase diminished I/R-induced upregulation of STAT3 phosphorylation and survivin expression and delayed recovery. Furthermore, I/R injury activated Notch-2 signaling, and a g-secretase inhibitor suppressed I/R-induced Notch-2 signaling, STAT3 phosphorylation, and survivin expression and delayed recovery. In MCT cells, inhibition of g-secretase similarly attenuated antimycin A-induced Notch-2 activation, upregulation of survivin, and phosphorylation of STAT3, but STAT3 kinase inhibition did not preventNotch-2 activation. Therefore, these data suggest that STAT3 phosphorylation and subsequent upregulation of survivin expression mediated by Notch-2 signaling in renal proximal tubule epithelial cells aid in the functional and structural recovery of the kidney from AKI.

Original languageEnglish (US)
Pages (from-to)2023-2033
Number of pages11
JournalJournal of the American Society of Nephrology
Volume24
Issue number12
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Nephrology

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