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Naturally Occurring Genetic Variants in Human Chromogranin A (CHGA) Associated with Hypertension as well as Hypertensive Renal Disease
Chen, Yuqing3; Rao, Fangwen1,2; Wen, Gen1,2; Gayen, Jiaur R.1,2; Zhang, Kuixing1,2; Vaingankar, Sucheta M.1,2; Biswas, Nilima1,2; Mahata, Manjula1,2; Friese, Ryan S.1,2; Fung, Maple M.1,2; Salem, Rany M.1,2; Nievergelt, Caroline1,2; Bhatnagar, Vibha1,2; Hook, Vivian Y.1,2,4; Ziegler, Michael G.1,2; Mahata, Sushil K.1,2; Hamilton, Bruce A.1,2,5; O&prime1; Connor, Daniel T.1,2,4,5
关键词Chga Hypertension Hypertensive Nephrosclerosis
刊名CELLULAR AND MOLECULAR NEUROBIOLOGY
2010-11-01
DOI10.1007/s10571-010-9600-2
30期:8页:1395-1400
收录类别SCI ; ISTP
文章类型Proceedings Paper
WOS标题词Science & Technology
类目[WOS]Cell Biology ; Neurosciences
研究领域[WOS]Cell Biology ; Neurosciences & Neurology
关键词[WOS]INHIBITORY PEPTIDE CATESTATIN ; BLOOD-PRESSURE ; CATECHOLAMINE RELEASE ; CARDIOVASCULAR REACTIVITY ; TYROSINE-HYDROXYLASE ; PROTEOLYTIC CLEAVAGE ; AUTONOMIC ACTIVITY ; IN-VIVO ; SECRETION ; STORAGE
英文摘要

Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive renal disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed both common and unusual variants in both the open reading frame and such regulatory regions as the proximal promoter and 3′-UTR. In chromaffin cell-transfected CHGA 3′-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 3′-UTR displayed statistical associations with hypertension. Genetic variation in the proximal CHGA promoter predicted glomerular filtration rate in healthy twins. However, for hypertensive renal damage, both end-stage renal disease and rate of progression of earlier disease were best predicted by variants in the 3′-UTR. Finally, mechanistic studies were undertaken initiated by the clue that CHGA promoter variation predicted circulating endothelin-1. In cultured endothelial cells, CHGA triggered co-release of not only the vasoconstrictor and pro-fibrotic endothelin-1, but also the pro-coagulant von Willebrand Factor and the pro-angiogenic angiopoietin-2. These findings, coupled with stimulation of endothelin-1 release from glomerular capillary endothelial cells by CHGA, suggest a plausible mechanism whereby genetic variation at the CHGA locus eventuates in alterations in human renal function. These results document the consequences of genetic variation at the CHGA locus for cardiorenal disease and suggest mechanisms whereby such variation achieves functional effects.

语种英语
WOS记录号WOS:000285947200037
引用统计
被引频次:6[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/50532
专题北京大学第一临床医学院_肾脏内科
作者单位1.Univ Calif San Diego, Dept Med 0838, La Jolla, CA 92093 USA
2.VASDHS, La Jolla, CA 92093 USA
3.Peking Univ, Hosp 1, Div Renal, Beijing 100034, Peoples R China
4.Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
5.Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
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GB/T 7714
Chen, Yuqing,Rao, Fangwen,Wen, Gen,et al. Naturally Occurring Genetic Variants in Human Chromogranin A (CHGA) Associated with Hypertension as well as Hypertensive Renal Disease[J]. CELLULAR AND MOLECULAR NEUROBIOLOGY,2010,30(8):1395-1400.
APA Chen, Yuqing.,Rao, Fangwen.,Wen, Gen.,Gayen, Jiaur R..,Zhang, Kuixing.,...&Connor, Daniel T..(2010).Naturally Occurring Genetic Variants in Human Chromogranin A (CHGA) Associated with Hypertension as well as Hypertensive Renal Disease.CELLULAR AND MOLECULAR NEUROBIOLOGY,30(8),1395-1400.
MLA Chen, Yuqing,et al."Naturally Occurring Genetic Variants in Human Chromogranin A (CHGA) Associated with Hypertension as well as Hypertensive Renal Disease".CELLULAR AND MOLECULAR NEUROBIOLOGY 30.8(2010):1395-1400.
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