Role of Renal ET-1 in Sodium Hemeostasis and Essential Hypertension

• Main Authors: Tusty-Jiuan Hsieh, 謝翠娟
• Other Authors: Juei-Hsiung Tsai
• Format: Others
• Language: zh-TW
• Published: 2000
• Online Access: http://ndltd.ncl.edu.tw/handle/jb637m

博士 === 高雄醫學大學 === 醫學研究所 === 88 === Endothelin-1 (ET-1) was initially discovered as a potent vasoconstrictor produced by cultured endothelial cells. Human ET-1 mRNA encodes a 212 amino acid prepropeptide that is cleaved by dibasic pair-specific endopeptidases to yield the 38 amino acid propeptide, big ET-1. Big ET-1 is converted both inside and outside the cell to mature ET-1 by endothelin-converting enzymes (ECEs). The biological activities of ET-1 are mediated by two distinct receptors, ETA and ETB receptors. ET-1 has now been shown to be produced ubiquitously and to exert actions on different tissues. Kidney, especially in inner medullary collecting ducts (IMCD), is one of the major regions where ET-1 production takes place. ET-1 has potent and complex actions in the kidney, whereby it causes renal vasoconstriction, leading to reductions of glomerular filtration rate and renal blood flow as well as sodium excretion and urinary volume. However, ET-1 also causes both diuretic and natriuretic actions by inhibiting the activities of Na+-K+-ATPase and water channel on renal tubular cells. Abnormalities of renal ET-1 synthesis and related sodium regulation disorders have been thought to be one of the etiologies of hypertension. We investigated the role of renal ET-1 in the regulation of daily sodium homeostasis and the possible contribution in the pathogenesis of essential hypertension (ETH). Urinary ET-1-like immunoreactivity (irET-1) was measured from 23 EHT patients and 11 normotensive controls. All study subjects received a controlled diet during an 8-day study period. On the 7th day, study subjects were given an intravenous infusion of 1,250 mL normal saline within 2 h. During the basal state, the urinary sodium and ET-1 excretions showed diurnal patterns in both the normal and hypertensive groups. Urinary irET-1 excretion rate correlated well with the urinary sodium excretion rate. After saline infusion, ten hypertensive patients showed nonexaggerated natriuresis, and the 24-h urinary irET-1 excretion was significantly lower than that of the control or the exaggeratedly natriuretic hypertensive patients. Our results suggest that renal ET-1 may be responsible for the renal handling of sodium homeostasis, and alteration of renal ET-1 synthesis may be a contributory factor in the pathogenesis of essential hypertension and salt sensitivity. To investigate the role of renal ET-1 synthesis in sodium homeostasis, we measured mRNA expressions, protein levels, enzyme activity and receptor binding of renal ET-1 system in DOCA and Salt treated rat model. Male Wistar rats were divided into control and DOCA-Salt treated groups. Urinary irET-1 significantly increased from the second day after DOCA and salt treatment, and correlated well with the urinary sodium excretion rate (r=0.81, p<0.001). Renal ECE activity, ET-1 and ECE-1 mRNA expressions were significantly increased in renal medullary area of DOCA-Salt rats. In situ hybridization and immunohistochemical studies showed that the increase of ET-1 synthesis was mainly localized in the IMCD. The maximum binding (Bmax) of ETB receptor also increased from the second day in renal medulla of the DOCA-Salt group. Our results suggest that the renal medullary ET-1 may be a natriuretic factor and may participate in the intra-renal regulation of salt homeostasis in pre-hypertensive DOCA-Salt rats. ET-1 gene polymorphisms have been investigated to involve in EH. In this study, we explored the different distribution of ET-1 genotypes between normotensive and hypertensive subjects. First, we found the distribution of T/T and G/T genotypes of c198 polymorphism was significantly higher in hypertensive group than that in normotensive group. It seems that the existence of T allele of ET-1 gene is a risk factor of hypertension. In conclusion, the renal tubular ET-1 system plays a role in the compensation for sodium overload and volume expansion. The disorder of ET-1 gene or ET-1 synthesis may be a risk factor to contribute hypertension.