Format

Send to

Choose Destination
Am J Pathol. 2015 May;185(5):1207-15. doi: 10.1016/j.ajpath.2015.02.003. Epub 2015 Mar 7.

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

Author information

1
Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.
2
Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.
3
Department of Pathology, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
4
Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
5
Research Center, Centre Hospitalier de l'Université de Montréal, University of Montréal, Montréal, Québec, Canada.
6
Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada; Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, London, Ontario, Canada. Electronic address: lakshman.gunaratnam@lhsc.on.ca.

Abstract

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 renal ischemia-reperfusion injury. We reveal that Kim-1 physically interacts with and inhibits cellular Gα12 activation after inflammatory stimuli, including reactive oxygen species, by blocking GTP binding to Gα12. Compared with Kim-1(+/+) mice, Kim-1(-/-) mice exhibited greater Gα12 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 Gα12.

PMID:
25759266
PMCID:
PMC4419204
DOI:
10.1016/j.ajpath.2015.02.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center