自发性高血压大鼠肾脏中内皮素受体亚型的功能与表达

Function and expression of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats.

作者信息

Hocher B, Rohmeiss P, Zart R, Diekmann F, Vogt V, Metz D, Fakhury M, Gretz N, Bauer C, Koppenhagen K, Neumayer H H, Distler A

机构信息

Department of Nephrology, Universitätsklinikum Charité der Humboldt Universität zu Berlin, City, Germany.

出版信息

Cardiovasc Res. 1996 Apr;31(4):499-510.

PMID:8689641

Abstract

OBJECTIVE

The renal endothelin system has been implicated in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). However, little is known about the function and cellular distribution of endothelin receptor subtypes in the kidneys of SHR.

METHODS

We analyzed the expression of endothelin receptor subtypes in the kidneys of 16-week-old SHR using Scatchard analysis, receptor autoradiography, Northern blot analysis and in situ hybridization. Wistar-Kyoto rats (WKY) served as controls. Furthermore, we investigated the effects of the mixed (A/B) endothelin receptor antagonist bosentan and the ETA receptor antagonist BQ 123 on mean arterial blood pressure (MAP), renal blood flow (RBF) and glomerular filtration rate (GFR) in conscious chronically instrumented rats.

RESULTS

In SHR, we found by receptor autoradiography an overexpression of the endothelin A receptor (ETA) in the glomeruli (2.2 +/- 0.4-fold; P < 0.05) and smooth muscle cells of intrarenal arteries (1.9 +/- 0.2-fold; P < 0.05) compared to age-matched WKY. In addition, our study revealed a pronounced upregulation of endothelin B receptor (ETB) in the glomeruli of SHR (5.6 +/- 0.8-fold; P < 0.01). Blockade of endothelin receptors in SHR with bosentan (A and B receptor blockade) as well as with BQ 123 (A receptor blockade) led to a significant decrease in MAP (-18.6 +/- 2.1 and -19 +/- 1.3 mmHg, respectively; P < 0.05 in both cases) and a significant increase in RBF (+2.8 +/- 0.5 and +3.1 +/- 0.37 ml/min, respectively; P < 0.05 in both cases). The blockade of both ETA and ETB by bosentan had no further effect on MAP reduction or RBF increase in SHR compared to the ETA blockade by BQ 123. The ETA antagonist BQ 123 had no effect on GFR either in SHR or in WKY, whereas the combined blockade of ETA and ETB by bosentan significantly decreased GFR in SHR by about 50% but not in WKY.

CONCLUSIONS

Our data demonstrated a correlation between the overexpression of vascular ETA receptors and the pronounced upregulation of glomerular ETB receptors in the kidneys of SHR and their impact on the regulation of renal blood flow, glomerular filtration rate and blood pressure in these animals.

摘要

目的

肾内皮素系统与自发性高血压大鼠（SHR）高血压的发生和维持有关。然而，关于SHR肾脏中内皮素受体亚型的功能和细胞分布知之甚少。

方法

我们使用Scatchard分析、受体放射自显影、Northern印迹分析和原位杂交技术，分析了16周龄SHR肾脏中内皮素受体亚型的表达。以Wistar-Kyoto大鼠（WKY）作为对照。此外，我们研究了混合（A/B）内皮素受体拮抗剂波生坦和ETA受体拮抗剂BQ 123对清醒慢性插管大鼠平均动脉血压（MAP）、肾血流量（RBF）和肾小球滤过率（GFR）的影响。

结果

通过受体放射自显影，我们发现与年龄匹配的WKY相比，SHR肾小球中内皮素A受体（ETA）过表达（2.2±0.4倍；P<0.05），肾内动脉平滑肌细胞中也过表达（1.9±0.2倍；P<0.05）。此外，我们的研究显示SHR肾小球中内皮素B受体（ETB）明显上调（5.6±0.8倍；P<0.01）。用波生坦（A和B受体阻断）以及BQ 123（A受体阻断）阻断SHR中的内皮素受体，导致MAP显著降低（分别为-18.6±2.1和-19±1.3 mmHg；两种情况均P<0.05），RBF显著增加（分别为+2.8±0.5和+3.1±0.37 ml/min；两种情况均P<0.05）。与BQ 123阻断ETA相比，波生坦同时阻断ETA和ETB对SHR降低MAP或增加RBF没有进一步影响。ETA拮抗剂BQ 123对SHR或WKY的GFR均无影响，而波生坦联合阻断ETA和ETB可使SHR的GFR显著降低约50%，但对WKY无此影响。