Netrin‐1 Over Expression Protects Kidney From Ischemia Reperfusion Injury By Suppressing Apoptosis

Abstract

Netrin‐1, a diffusible laminin‐related protein, is highly expressed in the kidney. The pathophysiological roles of netrin‐1 in kidney are unknown. To address directly, we used transgenic mice which over express chicken netrin‐1 in the kidney. Over expression was confirmed by real time RT‐PCR and western blot analysis. 8 weeks old WT and transgenic mice were then subjected to 26 minutes of renal ischemia followed perfusion for 72hrs. WT mice developed severe renal dysfunction by 24hrs whereas netrin‐1 transgenic mice were showed better renal function at 24hr (BUN: 56±3 vs. 151±10 and creatinine: 0.58±0.1 vs. 1.2±0.1, p<0.005). Functional improvement was associated with better preservation of morphology and peritubular capillaries, reduced inflammation, and reduced oxidative stress in transgenic mice kidney as compared to WT mice. In addition, both basal and reperfusion induced cell proliferation was dramatically increased in transgenic as seen by Ki67 staining. Interestingly, ischemia reperfusion induced a large increase of apoptosis in WT mice but not in netrin‐1 transgenic mice (319±16 vs. 1±0.3, p<0.0001). These results suggest that netrin‐1 protects renal tubular epithelial cells against ischemia reperfusion induced injury by increasing proliferation and suppressing apoptosis.