title: Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway.
abstract: AKI is associated with increased morbidity, mortality, and cost of care, and therapeutic options remain limited. Reactive oxygen species are critical for the genesis of ischemic AKI. Stanniocalcin-1 (STC1) suppresses superoxide generation through induction of uncoupling proteins (UCPs), and transgenic overexpression of STC1 inhibits reactive oxygen species and protects from ischemia/reperfusion (I/R) kidney injury. Our observations revealed high AMP-activated protein kinase (AMPK) activity in STC1 transgenic kidneys relative to wild-type (WT) kidneys; thus, we hypothesized that STC1 protects from I/R kidney injury through activation of AMPK. Baseline activity of AMPK in the kidney correlated with the expression of STCs, such that the highest activity was observed in STC1 transgenic mice followed (in decreasing order) by WT, STC1 knockout, and STC1/STC2 double-knockout mice. I/R in WT kidneys increased AMPK activity and the expression of STC1, UCP2, and sirtuin 3. Inhibition of AMPK by administration of compound C before I/R abolished the activation of AMPK, diminished the expression of UCP2 and sirtuin 3, and aggravated kidney injury but did not affect STC1 expression. Treatment of cultured HEK cells with recombinant STC1 activated AMPK and increased the expression of UCP2 and sirtuin 3, and concomitant treatment with compound C abolished these responses. STC1 knockout mice displayed high susceptibility to I/R, whereas pretreatment of STC1 transgenic mice with compound C restored the susceptibility to I/R kidney injury. These data suggest that STC1 is important for activation of AMPK in the kidney, which mediates STC1-induced expression of UCP2 and sirtuin 3 and protection from I/R.
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Jenny Szu-Chin
authors.initials: JS
authors.lastname: Pan
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Luping
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Belousova
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Lianghao
authors.initials: L
authors.lastname: Lu
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas;
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Sydney, Australia; and.
authors.forename: Roger
authors.initials: R
authors.lastname: Reddel
authors.affiliation: Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Sydney, Australia; and.
authors.forename: Andy
authors.initials: A
authors.lastname: Chang
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Huiming
authors.initials: H
authors.lastname: Ju
authors.affiliation: University of Western Ontario, Departments of Oncology and Biochemistry, London Regional Cancer Center, London, Ontario, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: DiMattia
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Division of Nephrology, Department of Medicine and sheikh@bcm.tmc.edu.
authors.forename: David
authors.initials: D
authors.lastname: Sheikh-Hamad
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism; D023421:Models, Animal; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology*; D056566:Sirtuin 3 / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D006023:Glycoproteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D013481:Superoxides; C051795:teleocalcin; D006861:Hydrogen Peroxide; D055372:AMP-Activated Protein Kinases; D056566:Sirtuin 3
keywords: ischemia-reperfusion; mitochondria; protection; reactive oxygen species; renal; renal injury; renal morphology