Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition.

Autor:	Wang Z; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Zeng C; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Villar VA; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Chen SY; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Konkalmatt P; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Wang X; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Asico LD; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Jones JE; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Yang Y; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Sanada H; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Felder RA; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Eisner GM; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Weir MR; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Armando I; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC., Jose PA; From the Division of Pediatric Nephrology, Department of Pediatrics, Georgetown University of School of Medicine, Washington, DC (Z.W.); Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China (C.Z.); Chongqing Institute of Cardiology, Chongqing, P.R. China; Division of Nephrology, Department of Medicine (V.A.M.V., X.W., L.D.A., J.E.J., Y.Y., M.R.W., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, MD; Department of Physiology and Pharmacology, University of Georgia, Athens, GA (S.-Y.C.); Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan (H.S.); Department of Pathology, The University of Virginia Health Sciences Center, Charlottesville (R.A.F.); Department of Medicine, Georgetown University Medical Center, Washington, DC (G.M.E.); Division of Renal Diseases and Hypertension, Department of Medicine (P.A.J.) and Department of Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC. pjose@mfa.gwu.edu.
Jazyk:	angličtina
Zdroj:	Hypertension (Dallas, Tex. : 1979) [Hypertension] 2016 Feb; Vol. 67 (2), pp. 325-34. Date of Electronic Publication: 2015 Dec 14.
DOI:	10.1161/HYPERTENSIONAHA.115.05962
Abstrakt:	The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4γ(142V) in mice results in hypertension because of impaired dopamine D1 receptor. Signaling through dopamine D1 receptor and angiotensin II type I receptor (AT1R) reciprocally modulates renal sodium excretion and blood pressure. Here, we demonstrate the ability of the hGRK4γ(142V) to increase the expression and activity of the AT1R. We show that hGRK4γ(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4γ(142V) mice. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining blood pressure homeostasis, and thus making the GRK4 a relevant therapeutic target to control blood pressure. (© 2015 American Heart Association, Inc.)
Databáze:	MEDLINE
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