title: Increased renal oxidative stress in salt-sensitive human GRK4γ486V transgenic mice.
abstract: We tested the hypothesis that salt-sensitive hypertension is caused by renal oxidative stress by measuring the blood pressure and reactive oxygen species-related proteins in the kidneys of human G protein-coupled receptor kinase 4γ (hGRK4γ) 486V transgenic mice and non-transgenic (Non-T) littermates on normal and high salt diets. High salt diet increased the blood pressure, associated with impaired sodium excretion, in hGRK4γ486V mice. Renal expressions of NOX isoforms were similar in both strains on normal salt diet but NOX2 was decreased by high salt diet to a greater extent in Non-T than hGRK4γ486V mice. Renal HO-2, but not HO-1, protein was greater in hGRK4γ486V than Non-T mice on normal salt diet and normalized by high salt diet. On normal salt diet, renal CuZnSOD and ECSOD proteins were similar but renal MnSOD was lower in hGRK4γ486V than Non-T mice and remained low on high salt diet. High salt diet decreased renal CuZnSOD in hGRK4γ486V but not Non-T mice and decreased renal ECSOD to a greater extent in hGRK4γ486V than Non-T mice. Renal SOD activity, superoxide production, and NOS3 protein were similar in two strains on normal salt diet. However, high salt diet decreased SOD activity and NOS3 protein and increased superoxide production in hGRK4γ486V mice but not in Non-T mice. High salt diet also increased urinary 8-isoprostane and 8-hydroxydeoxyguanosine to a greater extent in hGRK4γ486V than Non-T mice. hGRK4γwild-type mice were normotensive and hGRK4γ142V mice were hypertensive but both were salt-resistant and in normal redox balance. Chronic tempol treatment partially prevented the salt-sensitivity of hGRK4γ486V mice. Thus, hGRK4γ486V causes salt-sensitive hypertension due, in part, to defective renal antioxidant mechanisms.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Obstetrics & Gynecology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Diao
authors.affiliation: Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Laureano D
authors.initials: LD
authors.lastname: Asico
authors.affiliation: Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Van Anthony M
authors.initials: VAM
authors.lastname: Villar
authors.affiliation: Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Cuevas
authors.affiliation: Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Armando
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC, USA; Department of Pharmacology and Physiology, The George Washington University, Washington, DC, USA.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.affiliation: Department of Obstetrics & Gynecology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu, China; Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC, USA. Electronic address: xywang@gwu.edu.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D004195:Disease Models, Animal; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000235:genetics*; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000201:enzymology / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2 / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D055049:Salt Tolerance / Q000235:genetics; D012492:Salts / Q000633:toxicity; D013482:Superoxide Dismutase / Q000235:genetics*; D013481:Superoxides / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D054771:G-Protein-Coupled Receptor Kinase 4; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D000074662:NADPH Oxidase 2; D052250:Nitric Oxide Synthase Type III; D012492:Salts; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C496315:Nos3 protein, mouse; C496542:Hmox1 protein, mouse; C488842:Cybb protein, mouse; C517855:GRK4 protein, human
keywords: Hypertension; Kidney; NOS3; Oxidative stress; SOD; Tempol