Survivin mediates renal proximal tubule recovery from AKI.
AKI induces the renoprotective upregulation of survivin expression in kidney epithelial cells, but the underlying mechanisms 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 (survivin(ptKO)). Renal survivin expression increased substantially in response to ischemia-reperfusion (I/R) injury in control littermates but remained minimal in survivin(ptKO) mice. Functional and histologic data indicated similar degrees of renal injury in survivin(ptKO) and control mice 24 hours after reperfusion, but recovery was markedly delayed in survivin(ptKO) 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 γ-secretase inhibitor suppressed I/R-induced Notch-2 signaling, STAT3 phosphorylation, and survivin expression and delayed recovery. In MCT cells, inhibition of γ-secretase similarly attenuated antimycin A-induced Notch-2 activation, upregulation of survivin, and phosphorylation of STAT3, but STAT3 kinase inhibition did not prevent Notch-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.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
Jianchun
J
Chen
Jian-Kang
JK
Chen
Edward M
EM
Conway
Raymond C
RC
Harris
D058186:Acute Kidney Injury / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D002460:Cell Line; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051883:Receptor, Notch2 / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077022:Survivin; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000900:Anti-Bacterial Agents; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000077022:Survivin; D000968:Antimycin A