ER ribosomal-binding protein 1 regulates blood pressure and potassium homeostasis by modulating intracellular renin trafficking

Journal of Biomedical Science

Research

Wei-Chou Lin¹  Chin-Feng Hsuan²  Chih-Neng Hsu³  Jou-Wei Lin³  Siow-Wey Hee⁴  Hsiao-Lin Lee⁴  Meng-Lun Hsieh⁵  Lee-Ming Chuang⁶  Yi-Jen Hung⁷  Shu-Wha Lin⁸  Wen-Yi Li⁹  Vin-Cent Wu^1,10  Chii-Min Hwu^1,11  Gwo-Tsann Chuang^1,12  Wei-Shun Yang^1,13  Chu-Hsuan Chiu^1,14  Yi-Cheng Chang^1,15  Shih-Hua Lin^1,16  Sitt-Wai Fong^1,17  Patrick Ching-Ho Hsieh^1,17 

[1] Department of Pathology, National Taiwan University Hospital, 100, Taipei, Taiwan;Division of Cardiology, Department of Internal Medicine, E-Da Hospital, 824410, Kaohsiung, Taiwan;Division of Cardiology, Department of Internal Medicine, E-Da Dachang Hospital, 82445, Kaohsiung, Taiwan;School of Medicine, College of Medicine, I-Shou University, 840203, Kaohsiung, Taiwan;Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, 640, Yunlin, Taiwan;Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, 100, Taipei, Taiwan;Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, 100, Taipei, Taiwan;Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 32610, Gainesville, FL, USA;Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, 100, Taipei, Taiwan;Graduate Institute of Molecular Medicine, National Taiwan University, 100, Taipei, Taiwan;Graduate Institute of Clinical Medicine, National Taiwan University, 100, Taipei, Taiwan;Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, 100, Taipei, Taiwan;Division of Genomic Medicine, Research Center for Medical Excellence, Transgenic Mouse Models Core, National Taiwan University, 100, Taipei, Taiwan;Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, 640, Yunlin, Taiwan;Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, 100, Taipei, Taiwan;Faculty of Medicine, National Yang-Ming University School of Medicine, 112, Taipei, Taiwan;Division of Nephrology, Department of Medicine, Tri-Service General Hospital, 114, Taipei, Taiwan;Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, 100, Taipei, Taiwan;Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, 100, Taipei, Taiwan;Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, 100, Taipei, Taiwan;Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, 302, Hsin-Chu, Taiwan;Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, 100, Taipei, Taiwan;Institute of Biomedical Sciences, Academia Sinica, 115, Taipei, Taiwan;Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, 100, Taipei, Taiwan;Institute of Biomedical Sciences, Academia Sinica, 115, Taipei, Taiwan;Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, 100, Taipei, Taiwan;Graduate Institute of Molecular Medicine, National Taiwan University, 100, Taipei, Taiwan;Graduate Institute of Medical Science, National Defense Medical Center, 114, Taipei, Taiwan;Section of General Medicine, Department of Medicine, Taipei Veterans General Hospital, 111, Taipei, Taiwan;Institute of Biomedical Sciences, Academia Sinica, 115, Taipei, Taiwan;

关键词: Arrhythmia;    Blood pressure;    Cardiovascular disease;    Hyperkalemia;    Hyporeninemic hypoaldosteronism;    Renin–angiotensin–aldosterone system;    RRBP1;   

DOI  :  10.1186/s12929-023-00905-7

 received in 2022-10-31, accepted in 2023-02-07,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundGenome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown.MethodsTo identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia–Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model.ResultsIn the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion.ConclusionsRRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.Graphical Abstract

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 2

Fig. 2

Fig. 2

Fig. 2

Fig. 4

Fig. 9

Fig. 4