Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury

Kidney Int. 2012 Apr;81(8):751-61. doi: 10.1038/ki.2011.450. Epub 2012 Jan 11.


Loss of kidney function in renal ischemia/reperfusion injury is due to programmed cell death, but the contribution of necroptosis, a newly discovered form of programmed necrosis, has not been evaluated. Here, we identified the presence of death receptor-mediated but caspase-independent cell death in murine tubular cells and characterized it as necroptosis by the addition of necrostatin-1, a highly specific receptor-interacting protein kinase 1 inhibitor. The detection of receptor-interacting protein kinase 1 and 3 in whole-kidney lysates and freshly isolated murine proximal tubules led us to investigate the contribution of necroptosis in a mouse model of renal ischemia/reperfusion injury. Treatment with necrostatin-1 reduced organ damage and renal failure, even when administered after reperfusion, resulting in a significant survival benefit in a model of lethal renal ischemia/reperfusion injury. Unexpectedly, specific blockade of apoptosis by zVAD, a pan-caspase inhibitor, did not prevent the organ damage or the increase in urea and creatinine in vivo in renal ischemia/reperfusion injury. Thus, necroptosis is present and has functional relevance in the pathophysiological course of ischemic kidney injury and shows the predominance of necroptosis over apoptosis in this setting. Necrostatin-1 may have therapeutic potential to prevent and treat renal ischemia/reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Caspase Inhibitors
  • Cell Line
  • Cysteine Proteinase Inhibitors / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Jurkat Cells
  • Kidney / enzymology
  • Kidney / injuries*
  • Kidney / pathology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Necrosis
  • Oligopeptides / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology*
  • Reperfusion Injury / enzymology*
  • Reperfusion Injury / etiology
  • Reperfusion Injury / pathology*


  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Imidazoles
  • Indoles
  • Oligopeptides
  • Protein Kinase Inhibitors
  • benzyloxycarbonyl-valyl-alanyl-aspartic acid
  • necrostatin-1
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse