Cheng H F, Becker B N, Harris R C
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
J Clin Invest. 1996 Jun 15;97(12):2745-52. doi: 10.1172/JCI118729.
Systemic and/or locally produced angiotensin II stimulates salt and water reabsorption in the renal proximal tubule. In vivo, dopamine (DA) may serve as a counterregulatory hormone to angiotensin II's acute actions on the proximal tubule. We examined whether dopamine modulates AT1 receptor expression in cultured proximal tubule cells (RPTC) expressing DA1 receptors. Dopamine decreased basal RPTC AT1 receptor mRNA levels by 67 +/- 7% (n = 10; P < 0.005) and decreased 125I-angiotensin II binding by 41 +/- 7% (n = 4; P < 0.05). The DA1-specific agonist, SKF38393 decreased basal AT1 receptor mRNA levels (65 +/- 5% inhibition; n = 5; P < 0.025), and the DA1-specific antagonist, SCH23390 reversed dopamine's inhibition of AT1 receptor mRNA expression (24 +/- 10% inhibition; n = 8; NS) and angiotensin II binding (5 +/- 15%; n = 4; NS). DA2-specific antagonists were ineffective. In rats given L-DOPA in the drinking water for 5 d, there were decreases in both proximal tubule AT1 receptor mRNA expression (80 +/- 5%; n = 6; P < 0.005) and specific [125I] Ang II binding (control: 0.74 +/- 0.13 fmol/mg pro vs. 0.40 +/- 0.63 fmol/mg pro; n = 5; P < 0.05). In summary, dopamine, acting through DA1 receptors, decreased AT1 receptor expression in proximal tubule, an effect likely mediated by increased intracellular cAMP levels. Local dopamine production also led to decreased AT1 receptor expression, suggesting dopamine may reset sensitivity of the proximal tubule to angiotensin II.
全身和/或局部产生的血管紧张素II刺激肾近端小管对盐和水的重吸收。在体内，多巴胺（DA）可能作为一种反调节激素，对抗血管紧张素II对近端小管的急性作用。我们研究了多巴胺是否调节表达DA1受体的培养近端小管细胞（RPTC）中AT1受体的表达。多巴胺使基础RPTC的AT1受体mRNA水平降低67±7%（n = 10；P < 0.005），并使125I-血管紧张素II结合减少41±7%（n = 4；P < 0.05）。DA1特异性激动剂SKF38393降低基础AT1受体mRNA水平（抑制率65±5%；n = 5；P < 0.025），而DA1特异性拮抗剂SCH23390逆转多巴胺对AT1受体mRNA表达的抑制作用（抑制率24±10%；n = 8；无统计学意义）以及血管紧张素II结合（5±15%；n = 4；无统计学意义）。DA2特异性拮抗剂无效。给大鼠饮用含L-多巴的水5天，近端小管AT1受体mRNA表达（80±5%；n = 6；P < 0.005）和特异性[125I]血管紧张素II结合均降低（对照组：0.74±0.13 fmol/mg蛋白对0.40±0.63 fmol/mg蛋白；n = 5；P < 0.05）。总之，多巴胺通过DA1受体发挥作用，降低近端小管中AT1受体的表达，这一效应可能由细胞内cAMP水平升高介导。局部多巴胺的产生也导致AT1受体表达降低，提示多巴胺可能重置近端小管对血管紧张素II的敏感性。
