Zeng Chunyu, Wang Zheng, Asico Laureano D, Hopfer Ulrich, Eisner Gilbert M, Felder Robin A, Jose Pedro A
Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Kidney Int. 2005 Aug;68(2):623-31. doi: 10.1111/j.1523-1755.2005.00440.x.
The renin-angiotensin and endothelin systems interact to regulate blood pressure, in part, by affecting sodium transport in the kidney. Because angiotensin II type 1 (AT(1)) receptor activation increases ETB receptor expression in renal proximal tubule cells from Wistar-Kyoto (WKY) rat, we hypothesize that ETB receptor activation may also regulate AT(1) receptor expression. Furthermore, ETB receptor regulation of the AT(1) receptor may be different in the WKY and spontaneously hypertensive rat (SHR).
AT(1) and ETB receptors were studied in immortalized renal proximal tubule cells from WKY and SHRs, using immunoblotting, confocal microscopic colocalization, and immunoprecipitation.
In WKY renal proximal tubule cells, an ETB receptor agonist, BQ3020, decreased AT(1) receptor protein in a time- and concentration-dependent manner [median effective concentration (EC(50)) = 3.2 x 10(-10) mol/L, t(1/2)= 15 hours]. The inhibitory effect of BQ3020 (10(-8) mol/L/24 hours) on AT(1) receptor protein was blocked by an ETB receptor antagonist (BQ788). However, BQ3020 (10(-8) mol/L/24 hours) increased ETB receptor protein in WKY renal proximal tubule cells. In contrast, in SHR renal proximal tubule cells, BQ3020 (10(-8) mol/L/24 hours) no longer affected AT(1) or ETB receptor protein. AT(1)/ETB receptors colocalized and coimmunoprecipitated in WKY and SHRs. BQ3020 (10(-8) mol/L/15 minutes) treatment had no effect on AT(1)/ETB coimmunoprecipitation in WKY but decreased it in SHRs. BQ3020 (10(-8) mol/L/15 minutes) treatment increased AT(1) receptor phosphorylation in WKY, but decreased it in SHRs.
ETB receptors regulate AT(1) receptors by direct physical receptor interaction and receptor expression. An impaired ETB receptor regulation of the AT(1) receptor may participate in the pathogenesis of high blood pressure in the SHR.
肾素 - 血管紧张素系统和内皮素系统相互作用，部分通过影响肾脏中的钠转运来调节血压。由于血管紧张素II 1型（AT(1)）受体激活会增加Wistar - Kyoto（WKY）大鼠肾近端小管细胞中ETB受体的表达，我们推测ETB受体激活也可能调节AT(1)受体的表达。此外，WKY大鼠和自发性高血压大鼠（SHR）中ETB受体对AT(1)受体的调节可能有所不同。
使用免疫印迹、共聚焦显微镜共定位和免疫沉淀技术，对WKY大鼠和SHR的永生化肾近端小管细胞中的AT(1)和ETB受体进行研究。
在WKY肾近端小管细胞中，ETB受体激动剂BQ3020以时间和浓度依赖性方式降低AT(1)受体蛋白水平[半数有效浓度（EC(50)）= 3.2×10(-10) mol/L，半衰期（t(1/2)）= 15小时]。ETB受体拮抗剂（BQ788）可阻断BQ3020（10(-8) mol/L/24小时）对AT(1)受体蛋白的抑制作用。然而，BQ3020（10(-8) mol/L/24小时）可增加WKY肾近端小管细胞中的ETB受体蛋白水平。相比之下，在SHR肾近端小管细胞中，BQ3020（10(-8) mol/L/24小时）不再影响AT(1)或ETB受体蛋白水平。AT(1)/ETB受体在WKY大鼠和SHR中共定位且可进行共免疫沉淀。BQ3020（10(-8) mol/L/15分钟）处理对WKY大鼠的AT(1)/ETB共免疫沉淀无影响，但可降低SHR中的共免疫沉淀水平。BQ3020（10(-8) mol/L/15分钟）处理可增加WKY大鼠中AT(1)受体的磷酸化水平，但可降低SHR中的磷酸化水平。
ETB受体通过直接的物理受体相互作用和受体表达来调节AT(1)受体。ETB受体对AT(1)受体调节受损可能参与了SHR高血压的发病机制。
