Inhibition of JAK2 protects renal endothelial and epithelial cells from oxidative stress and cyclosporin A toxicity

Kidney Int. 2009 Jan;75(2):227-34. doi: 10.1038/ki.2008.487. Epub 2008 Sep 24.

Abstract

Cyclosporin A is an immunosuppressant drug widely used in solid organ transplantation, but it has nephrotoxic properties that promote oxidative stress. The JAK2/STAT pathway has been implicated in both cell protection and cell injury; therefore, we determined a role of JAK2 in oxidative stress-mediated renal cell injury using pathophysiologically relevant oxidative challenges. The AG490 JAK2 inhibitor and overexpression of a dominant negative JAK2 protein protected endothelial and renal epithelial cells in culture against peroxide, superoxide anion and cyclosporin A induced cell death while reducing intracellular oxidation in cells challenged with peroxide and cyclosporin A. The decrease in Bcl2 expression and caspase 3 activation, induced by oxidative stress, was prevented by AG490. In mouse models of ischemia/reperfusion and cyclosporin A nephrotoxicity, AG490 decreased peritubular capillary and tubular cell injury. Our study shows that JAK2 inhibition is a promising renoprotective strategy defending endothelial and tubular cells from cyclosporin A- and oxidative stress-induced death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclosporine / toxicity*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / physiology
  • Kidney / cytology*
  • Mice
  • Oxidative Stress / drug effects*
  • Protective Agents / pharmacology
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / prevention & control
  • Tyrphostins / pharmacology*

Substances

  • Protective Agents
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Cyclosporine
  • Janus Kinase 2