GRK4 R65L causes salt-sensitive hypertension by augmenting renal Hao2-mediated oxidative stress via increasing the phosphorylation of TPI1 and promoting H3K27ac expression

Fuwei Zhang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Jindong Wan, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Cardiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, PR China.
Lianghong Jiang, Clinical Medical College of Southwest Medical University, Luzhou, PR China; Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Xiaoqian Lin, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Lin Chen, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Muqing Shao, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Jiayao Chen, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Luning Wang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Shuo Zheng, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Hongmei Ren, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Caiyu Chen, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Pedro A. Jose, Division of Renal Diseases & Hypertension, Department of Medicine and Pharmacology/Physiology, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China. Electronic address: zengchunyu@tmmu.edu.cn.
Jian Yang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China. Electronic address: jianyang@hospital.cqmu.edu.cn.

Document Type

Journal Article

Publication Date

12-15-2025

Journal

Free radical biology & medicine

Volume

244

DOI

10.1016/j.freeradbiomed.2025.12.017

Keywords

GRK4 R65L; Kidney; Long chain L-2-hydroxy acid oxidase 2; Oxidative stress; Salt-sensitive hypertension; Triosephosphate isomerase 1

Abstract

G protein-coupled receptor kinase 4 (GRK4) plays a vital role in the regulation of blood pressure. Several GRK4 gene variants have attracted attention because of their association with hypertension. However, the role of GRK4 R65L in hypertension is still unclear. In the present study, we report that global and renal tubule-targeted GRK4 R65L over-expression in mice caused salt-sensitive hypertension, accompanied by a rightward shift of the plot of urine sodium excretion against systolic blood pressure, that were improved by AAV9-mediated renal GRK4 depletion. RNA sequencing showed that the expression of the long chain L-2-hydroxyacid oxidase 2 (Hao2) gene ranked first in up-regulated candidates involved in the regulation of sodium-water metabolism. The salt-sensitive hypertension and increased renal oxidative stress in GRK4 R65L mice were mitigated by AAV9-mediated renal Hao2 depletion or administration of the potent antioxidant tempol. Immunoprecipitation-mass spectrometry showed an increased interaction between triosephosphate isomerase 1 (TPI1) and GRK4 in the kidneys of high salt-fed GRK4 R65L mice, accompanied by increased TPI1 phosphorylation and nuclear translocation, which were decreased, along with renal Hao2 expression, after GRK4 depletion. Renal H3K27ac levels and binding to the Hao2 promoter were increased but the levels of nuclear dihydroxyacetone phosphate (DHAP), a downstream molecule of TPI1, were decreased in high salt-fed GRK4 R65L mice. DHAP reduced the levels of H3K27ac and Hao2 in GRK4 R65L transfected-HK-2 cells. The H3K27ac inhibitor C646 mitigated the salt-sensitive hypertension in GRK4 R65L mice, accompanied by decreased H3K27ac and Hao2 expressions, and oxidative stress. Our results demonstrated that in high salt fed-GRK4 R65L mice, elevated renal TPI1 nuclear phosphorylation decreased DHAP levels and increased H3K27ac expression, which increased Hao2 expression and oxidative stress, caused a rightward shift of the pressure-natriuresis plot, and subsequently caused salt-sensitive hypertension.

Department

Medicine

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