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Kidney injury molecule-1 protects against G?12 activation and tissue damage in renal ischemia-reperfusion injury.


ABSTRACT: Ischemic acute kidney injury is a serious untreatable condition. Activation of the G protein ?12 (G?12) subunit by reactive oxygen species is a major cause of tissue damage during renal ischemia-reperfusion injury. Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein that is highly up-regulated during acute kidney injury, but the physiologic significance of this up-regulation is unclear. Here, we report for the first time that Kim-1 inhibits G?12 activation and protects mice against renal ischemia-reperfusion injury. We reveal that Kim-1 physically interacts with and inhibits cellular G?12 activation after inflammatory stimuli, including reactive oxygen species, by blocking GTP binding to G?12. Compared with Kim-1(+/+) mice, Kim-1(-/-) mice exhibited greater G?12 and downstream Src activation both in primary tubular epithelial cells after in vitro stimulation with H2O2 and in whole kidneys after unilateral renal artery clamping. Finally, we show that Kim-1-deficient mice had more severe kidney dysfunction and tissue damage after bilateral renal artery clamping, compared with wild-type mice. Our results suggest that KIM-1 is an endogenous protective mechanism against renal ischemia-reperfusion injury through inhibition of G?12.

SUBMITTER: Ismail OZ 

PROVIDER: S-EPMC4419204 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Kidney injury molecule-1 protects against Gα12 activation and tissue damage in renal ischemia-reperfusion injury.

Ismail Ola Z OZ   Zhang Xizhong X   Wei Junjun J   Haig Aaron A   Denker Bradley M BM   Suri Rita S RS   Sener Alp A   Gunaratnam Lakshman L  

The American journal of pathology 20150307 5


Ischemic acute kidney injury is a serious untreatable condition. Activation of the G protein α12 (Gα12) subunit by reactive oxygen species is a major cause of tissue damage during renal ischemia-reperfusion injury. Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein that is highly up-regulated during acute kidney injury, but the physiologic significance of this up-regulation is unclear. Here, we report for the first time that Kim-1 inhibits Gα12 activation and protects mice against  ...[more]

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