title: Kidney injury molecule-1 protects against Gα12 activation and tissue damage in renal ischemia-reperfusion injury.
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.
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Ola Z
authors.initials: OZ
authors.lastname: Ismail
authors.affiliation: Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Xizhong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Junjun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Pathology, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Haig
authors.affiliation: Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Denker
authors.affiliation: Research Center, Centre Hospitalier de l'Université de Montréal, University of Montréal, Montréal, Québec, Canada.
authors.forename: Rita S
authors.initials: RS
authors.lastname: Suri
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Alp
authors.initials: A
authors.lastname: Sener
authors.affiliation: 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.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Gunaratnam
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D000072596:Hepatitis A Virus Cellular Receptor 1; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
chemical_list: C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D044365:GTP-Binding Protein alpha Subunits, G12-G13