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

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...

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Vydané v:Kidney international Ročník 81; číslo 8; s. 751 - 761
Hlavní autori: Linkermann, Andreas, Bräsen, Jan H., Himmerkus, Nina, Liu, Shuya, Huber, Tobias B., Kunzendorf, Ulrich, Krautwald, Stefan
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Basingstoke Elsevier Inc 01.04.2012
Nature Publishing Group
Elsevier Limited
Predmet:
Animals
Apoptosis
Biological and medical sciences
Cardiology. Vascular system
Caspase Inhibitors
cell death
Cell Line
Cysteine Proteinase Inhibitors - pharmacology
Humans
Imidazoles - pharmacology
Indoles - pharmacology
ischemia
ischemia–reperfusion
ischemic renal failure
Jurkat Cells
Kidney - enzymology
Kidney - injuries
Kidney - pathology
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - enzymology
Kidney Tubules, Proximal - pathology
Male
Medical sciences
Mice
Mice, Inbred C57BL
Necrosis
Nephrology. Urinary tract diseases
Nephropathies. Renovascular diseases. Renal failure
Oligopeptides - pharmacology
Protein Kinase Inhibitors - pharmacology
Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors
Receptor-Interacting Protein Serine-Threonine Kinases - physiology
Renovascular diseases
Reperfusion Injury - enzymology
Reperfusion Injury - etiology
Reperfusion Injury - pathology
tubule cells
cell death
tubule cells
ischemia–reperfusion
ischemia
ischemic renal failure
Kidney disease
Nephrology
Urinary system disease
Enzyme
Transferases
Ischemia reperfusion
Non-specific serine/threonine protein kinase
Cardiovascular disease
Kidney
Urology
Vascular disease
Renal tubule
Urinary system
Cell death
Renal failure
ischemia―reperfusion
Receptor protein
Renal ischemia reperfusion injury
Apoptosis
ISSN:0085-2538, 1523-1755, 1523-1755
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Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0085-2538
1523-1755
1523-1755
DOI:10.1038/ki.2011.450