Inhibition of RIPK1 or RIPK3 kinase activity post ischemia-reperfusion reduces the development of chronic kidney injury
Journal Title
Biochemical Journal
Publication Type
Dec 20 epub ahead of print
Abstract
Ischemia-reperfusion injury (IRI) occurs when the blood supply to an organ is temporarily reduced and then restored. Kidney IRI is a form of acute kidney injury, which often progresses to kidney fibrosis. Necroptosis is a regulated necrosis pathway that has been implicated in kidney IRI. Necroptotic cell death involves recruitment of the RIPK1 and RIPK3 kinases and activation of the terminal effector, the MLKL pseudokinase. Phosphorylated MLKL causes cell death by plasma membrane rupture, driving "necroinflammation". Owing to their apical role in the pathway, RIPK1 and RIPK3 have been implicated in the development of kidney fibrosis. Here, we used a mouse model of unilateral kidney IRI to assess whether inhibition of RIPK1 or RIPK3 kinase activity reduces acute kidney injury and the progression to kidney fibrosis. Mice treated with the RIPK1 inhibitor Nec-1s, either before or after IR, showed reduced kidney injury at 24 hours compared to controls, whereas no protection was offered by the RIPK3 inhibitor GSK´872. In contrast, treatment with either inhibitor from days 3-9 post-IR reduced the degree of kidney fibrosis at day 28. These findings further support the role of necroptosis in IRI and provide important validation for the contribution of both RIPK1 and RIPK3 catalytic activities in the progression of kidney fibrosis. Targeting the necroptosis pathway could be a promising therapeutic strategy to mitigate kidney disease following IR.
Publisher
Portland Press
Keywords
acute kidney injury; ischaemia-reperfusion injury; kidney fibrosis; kinase inhibitor; programmed necrosis
Research Division(s)
Inflammation
PubMed ID
39705008
Open Access at Publisher's Site
https://doi.org/10.1042/BCJ20240569
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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