Netrin-1 overexpression protects kidney from ischemia reperfusion injury by suppressing apoptosis

Weiwei Wang, William Brian Reeves, Laurent Pays, Patrick Mehlen, Ganesan Ramesh

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Netrin-1, a diffusible laminin-related protein, is highly expressed in the kidney. However, the pathophysiological roles of netrin-1 in the kidney are unknown. To address this question directly, we used transgenic mice that overexpress chicken netrin-1 in the kidney. Netrin-1 overexpression was confirmed by real-time RT-PCR and Western blot analysis. Eight-week-old wild-type and transgenic mice were subjected to 26 minutes of renal ischemia followed by reperfusion for 72 hours. Wild-type mice developed more severe renal dysfunction by 24 hours than netrin-1 transgenic mice. Functional improvement was associated with better preservation of morphology, reduced cytokine expression, and reduced oxidative stress in the kidney of transgenic mice as compared with wild-type mice. In addition, both basal and reperfusion-induced cell proliferation were dramatically increased in transgenic kidneys as determined by Ki-67 staining. Interestingly, ischemia reperfusion induced a large increase in apoptosis in wild-type mice but not in netrin-1 transgenic mice that was associated with reduced caspase-3 activation in the transgenic kidney. These results suggest that netrin-1 protects renal tubular epithelial cells against ischemia reperfusion-induced injury by increasing proliferation and suppressing apoptosis.

Original languageEnglish (US)
Pages (from-to)1010-1018
Number of pages9
JournalAmerican Journal of Pathology
Volume175
Issue number3
DOIs
StatePublished - Sep 1 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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