title: Superoxide and hydrogen peroxide counterregulate myogenic contractions in renal afferent arterioles from a mouse model of chronic kidney disease.
abstract: Myogenic contractions protect kidneys from barotrauma but are impaired in chronic kidney disease (CKD). Since myogenic contractions are enhanced by superoxide but impaired by hydrogen peroxide, we tested the hypothesis that they are counterregulated by superoxide and H2O2from NOX2/p47phox and/or NOX4/POLDIP2 in CKD. Myogenic contraction in isolated perfused afferent arterioles from mice with surgical 5/6 nephrectomy or sham operations fed a 6% sodium chloride diet was measured directly while superoxide and H2O2were measured by fluorescence microscopy. Compared to sham-operated animals, an increase in perfusion pressure of arterioles from CKD mice doubled superoxide (21 versus 11%), increased H2O2seven-fold (29 versus 4%), and reduced myogenic contractions profoundly (-1 versus -14%). Myogenic contractions were impaired further by PEG-superoxide dismutase or in arterioles from p47phox-/- (versus wild type) mice but became supra-normal by PEG-catalase or in mice with transgenic expression of catalase in vascular smooth muscle cells (-11 versus -1%). Single arterioles from mice with CKD expressed over 40% more mRNA and protein for NOX4 and POLDIP2. Myogenic responses in arterioles from POLDIP2 +/- (versus wild type) mice with CKD had over an 85% reduction in H2O2, but preserved superoxide and a normal myogenic response. Tempol administration to CKD mice for 3 months decreased afferent arteriolar superoxide and H2O2and maintained myogenic contractions. Thus, afferent arteriolar superoxide generated by NOX2/p47phox opposes H2O2generated by NOX4/POLDIP2 whose upregulation in afferent arterioles from mice with CKD accounts for impaired myogenic contractions.
authors.affiliation: Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, DC, USA.
authors.forename: Lingli
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, DC, USA; Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: En Yin
authors.initials: EY
authors.lastname: Lai
authors.affiliation: Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, DC, USA.
authors.forename: Zaiming
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, DC, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Solis
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: Division of Renal Diseases & Hypertension, Department of Medicine and Department of Pharmacology and Physiology, George Washington University; Washington, DC, USA.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.affiliation: Lombardi Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
authors.affiliation: Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, DC, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Welch
authors.affiliation: Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, DC, USA. Electronic address: wilcoxch@georgetown.edu.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
mesh_terms: D000818:Animals; D001160:Arterioles / Q000201:enzymology / Q000503:physiopathology*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D024101:Mitochondrial Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology*; D000074662:NADPH Oxidase 2 / Q000378:metabolism; D000074663:NADPH Oxidase 4 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010477:Perfusion; D011092:Polyethylene Glycols / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000473:pathology*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D003497:Cyclic N-Oxides; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D013113:Spin Labels; C070295:catalase-polyethylene glycol; C514737:mitogenin 1 protein, mouse; D013481:Superoxides; D011092:Polyethylene Glycols; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C060505:neutrophil cytosolic factor 1; C001803:tempol
keywords: oxidative stress; reduced renal mass; renal autoregulation; tempol