Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China.
J Hypertens. 2012 Jun;30(6):1176-84. doi: 10.1097/HJH.0b013e3283532099.
The renin-angiotensin (Ang) system controls blood pressure, in part, by regulating renal tubular sodium transport. In the kidney, activation of the angiotensin II type 1 (AT(1)) receptor increases renal sodium reabsorption, whereas the angiotensin II type 2 (AT(2)) receptor produces the opposite effect. We hypothesized that the AT(2) receptor regulates AT(1) receptor expression and function in the kidney.
In immortalized renal proximal tubule (RPT) cells from Wistar-Kyoto rats, CGP42112, an AT(2) receptor agonist, decreased AT(1) receptor mRNA and protein expression (P < 0.05), as assessed by reverse transcriptase-polymerase chain reaction and immunoblotting. The inhibitory effect of the AT(2) receptor on AT(1) receptor expression was blocked by the AT(2) receptor antagonist, PD123319 (10 (-6)mol/l), the nitric oxide synthase inhibitor N(w)-nitro-L-arginine methyl ester (10(-4) mol/l), or the nitric oxide-dependent soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10(-5) mol/l), indicating that both nitric oxide and cyclic guanosine monophosphate (cGMP) were involved in the signaling pathway. Furthermore, CGP42112 decreased Sp1 serine phosphorylation and reduced the binding of Sp1 to AT(1) receptor DNA. Stimulation with Ang II (10(-11) mol/l per 30 min) enhanced Na(+)-K(+)-ATPase activity in RPT cells, which was prevented by pretreatment with CGP42112 (10(-7) mol/l per 24 h) (P < 0.05). The above-mentioned results were confirmed in RPT cells from AT(2) receptor knockout mice; AT(1) receptor expression and Ang II-stimulated Na-K-ATPase activity were greater in these cells than in RPT cells from wild-type mice (P < 0.05). AT(1)/AT(2) receptors co-localized and co-immunoprecipitated in RPT cells; short-term CGP42112 (10 mol/l per 30 min) treatment increased AT(1)/AT(2) receptor co-immunoprecipitation (P < 0.05).
These results indicate that the renal AT(2) receptor, via nitric oxide/cGMP/Sp1 pathway, regulates AT(1 )receptor expression and function, which may be important in the regulation of sodium excretion and blood pressure.
肾素-血管紧张素（Ang）系统通过调节肾小管钠转运来控制血压。在肾脏中，血管紧张素 II 型 1（AT（1））受体的激活增加了肾脏对钠的重吸收，而血管紧张素 II 型 2（AT（2））受体则产生相反的效果。我们假设 AT（2）受体调节肾脏中的 AT（1）受体表达和功能。
在来自 Wistar-Kyoto 大鼠的永生化肾近端小管（RPT）细胞中，血管紧张素 II 型 2（AT（2））受体激动剂 CGP42112 通过逆转录聚合酶链反应和免疫印迹降低 AT（1）受体 mRNA 和蛋白表达（P < 0.05）。AT（2）受体拮抗剂 PD123319（10-6mol/l）、一氧化氮合酶抑制剂 N（w）-硝基-L-精氨酸甲酯（10-4mol/l）或一氧化氮依赖性可溶性鸟苷酸环化酶抑制剂 1H-[1,2,4]恶二唑-[4,3-a]喹喔啉-1-酮（10-5mol/l）阻断了 AT（2）受体对 AT（1）受体表达的抑制作用，表明一氧化氮和环鸟苷酸（cGMP）都参与了信号通路。此外，CGP42112 降低了 Sp1 丝氨酸磷酸化，并减少了 Sp1 与 AT（1）受体 DNA 的结合。用 CGP42112（10-7mol/l 预处理 24 小时）预处理可防止 Ang II（10-11mol/l 每 30 分钟）刺激 RPT 细胞中 Na（+）-K（+）-ATP 酶活性增加（P < 0.05）。在 AT（2）受体敲除小鼠的 RPT 细胞中证实了上述结果；这些细胞中的 AT（1）受体表达和 Ang II 刺激的 Na-K-ATP 酶活性大于来自野生型小鼠的 RPT 细胞（P < 0.05）。AT（1）/AT（2）受体在 RPT 细胞中共定位和共免疫沉淀；短期 CGP42112（10mol/l 每 30 分钟）处理增加了 AT（1）/AT（2）受体共免疫沉淀（P < 0.05）。
这些结果表明，肾脏 AT（2）受体通过一氧化氮/cGMP/Sp1 途径调节 AT（1）受体表达和功能，这可能在调节钠排泄和血压方面很重要。
