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

Am J Pathol. 2009 Sep;175(3):1010-8. doi: 10.2353/ajpath.2009.090224. Epub 2009 Aug 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Proliferation
  • Chickens
  • Gene Expression Regulation
  • Kidney / blood supply
  • Kidney / metabolism*
  • Kidney / pathology
  • Mice
  • Mice, Transgenic
  • Nerve Growth Factors / biosynthesis*
  • Nerve Growth Factors / genetics
  • Netrin-1
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Proteins / biosynthesis*
  • Tumor Suppressor Proteins / genetics


  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Tumor Suppressor Proteins
  • Netrin-1