title: Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition.
abstract: 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.
authors.affiliation: 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.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Van Anthony M
authors.initials: VA
authors.lastname: Villar
authors.affiliation: 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.
authors.forename: Shi-You
authors.initials: SY
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Prasad
authors.initials: P
authors.lastname: Konkalmatt
authors.affiliation: 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.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Laureano D
authors.initials: LD
authors.lastname: Asico
authors.affiliation: 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.
authors.forename: John E
authors.initials: JE
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sanada
authors.affiliation: 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.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
authors.affiliation: 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.
authors.forename: Gilbert M
authors.initials: GM
authors.lastname: Eisner
authors.affiliation: 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.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Weir
authors.affiliation: 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.
authors.forename: Ines
authors.initials: I
authors.lastname: Armando
authors.affiliation: 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.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D000075222:Essential Hypertension; D005260:Female; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015151:Immunoblotting; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D012313:RNA; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; D056284:Histone Deacetylase 1; C081643:candesartan
keywords: G-protein–coupled receptor kinase 4; angiotensin II type 1 receptor; dopamine D1 receptors; histone deacetylase; hypertension; knockout mice