Kidney injury molecule-1 protects against Gα12 activation and tissue damage in renal ischemia-reperfusion injury.
Am J Pathol
; 185(5): 1207-15, 2015 May.
Article
em En
| MEDLINE
| ID: mdl-25759266
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão
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Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP
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Injúria Renal Aguda
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Proteínas de Membrana
Limite:
Animals
Idioma:
En
Revista:
Am J Pathol
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Canadá