Overexpression of stanniocalcin-1 inhibits reactive oxygen species and renal ischemia/reperfusion injury in mice.
Reactive oxygen species, endothelial dysfunction, inflammation, and mitogen-activated protein kinases have important roles in the pathogenesis of ischemia/reperfusion kidney injury. Stanniocalcin-1 (STC1) suppresses superoxide generation in many systems through the induction of mitochondrial uncoupling proteins and blocks the cytokine-induced rise in endothelial permeability. Here we tested whether transgenic overexpression of STC1 protects from bilateral ischemia/reperfusion kidney injury. This injury in wild-type mice caused a halving of the creatinine clearance; severe tubular vacuolization and cast formation; increased infiltration of macrophages and T cells; higher vascular permeability; greater production of superoxide and hydrogen peroxide; and higher ratio of activated extracellular regulated kinase/activated Jun-N-terminal kinase and p38, all compared to sham-treated controls. Mice transgenic for human STC1 expression, however, had resistance to equivalent ischemia/reperfusion injury indicated as no significant change from controls in any of these parameters. Tubular epithelial cells in transgenic mice expressed higher mitochondrial uncoupling protein 2 and lower superoxide generation. Pre-treatment of transgenic mice with paraquat, a generator of reactive oxygen species, before injury restored the susceptibility to ischemia/reperfusion kidney injury, suggesting that STC1 protects by an anti-oxidant mechanism. Thus, STC1 may be a therapeutic target for ischemia/reperfusion kidney injury.
Department of Medicine, Division of Nephrology, Baylor College of Medicine, The University of Western Ontario, London, Ontario, Canada.
Luping
L
Huang
Tatiana
T
Belousova
Minyi
M
Chen
Gabriel
G
DiMattia
Dajun
D
Liu
David
D
Sheikh-Hamad
D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D002199:Capillary Permeability; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000293:injuries / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000473:pathology; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
D006023:Glycoproteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; C051795:teleocalcin; D010269:Paraquat