- 作者: Chu-Hsuan Chiu, Chin-Feng Hsuan, Shih-Hua Lin, Yi-Jen Hung, Chii-Min Hwu, Siow-Wey Hee, Shu-Wha Lin, Sitt-Wai Fong, Patrick Ching-Ho Hsieh, Wei-Shun Yang, Wei-Chou Lin, Hsiao-Lin Lee, Meng-Lun Hsieh, Wen-Yi Li, Jou-Wei Lin, Chih-Neng Hsu, Vin-Cent Wu, Gwo-Tsann Chuang, Yi-Cheng Chang & Lee-Ming Chuang
- 作者服務機構: 1.Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA 2.Department of Pathology, National Taiwan University Hospital, Taipei, 100, Taiwan 3.Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, 100, Taiwan 4.Division of Cardiology, Department of Internal Medicine, E-Da Dachang Hospital, Kaohsiung, 82445, Taiwan 5.Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, 824410, Taiwan 6.Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, 640, Taiwan 7.Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan 8.Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, 100, Taiwan 9.Division of Genomic Medicine, Research Center for Medical Excellence, Transgenic Mouse Models Core, National Taiwan University, Taipei, 100, Taiwan 10.Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, 640, Taiwan 11.Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, 302, Taiwan 12.Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan 13.Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, 114, Taiwan 14.Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, 112, Taiwan 15.Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, 100, Taiwan 16.Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, 100, Taiwan 17.Graduate Institute of Medical Science, National Defense Medical Center, Taipei, 114, Taiwan 18.Graduate Institute of Molecular Medicine, National Taiwan University, Taipei, 100, Taiwan 19.Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan 20.School of Medicine, College of Medicine, I-Shou University, Kaohsiung, 840203, Taiwan 21.Section of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, 111, Taiwan
- 中文摘要:
- 英文摘要:
Background
Genome-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.
Methods
To 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.
Results
In 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.
Conclusions
RRBP1 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. - 中文關鍵字:
- 英文關鍵字: Arrhythmia, Blood pressure, Cardiovascular disease, Hyperkalemia, Hyporeninemic hypoaldosteronism, Renin–angiotensin–aldosterone system, RRBP1