Umrani Dhananjay N, Banday Anees A, Hussain Tahir, Lokhandwala Mustafa F
Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Tex 77204, USA.
Hypertension. 2002 Dec;40(6):880-5. doi: 10.1161/01.hyp.0000039963.01288.d3.
Earlier we have reported a defective dopamine D1-like receptor function, which was accompanied by a decrease in D1 receptor numbers and the inability of dopamine to inhibit Na,K-ATPase and Na,H-exchanger in proximal tubules of hyperinsulinemic obese Zucker rats. The present study was designed to test the hypothesis that the defect in dopamine receptor function is a result of hyperinsulinemia in obese rats. We designed experiments to study D1 receptor function in obese Zucker rats treated with rosiglitazone, as it lowers plasma insulin by improving insulin sensitivity. A group of untreated lean and obese rats served as controls. Rosiglitazone treatment (10 mg/kg orally, 4 weeks) caused significant decreases in plasma insulin, blood glucose, and blood pressure while causing an increase in renal sodium excretion compared with untreated obese rats. In the isolated proximal tubules obtained from untreated lean rats, dopamine caused concentration-dependent inhibition of the Na,K-ATPase activity, but this inhibitory effect was absent in untreated obese rats. In rosiglitazone-treated obese rats, the inhibitory effect of dopamine on Na,K-ATPase was significantly restored. This was accompanied by a complete restoration of D1 receptor numbers in proximal tubular membranes of treated obese rats. In another set of experiments, treatment of primary proximal tubule epithelial cells in culture medium with insulin caused a significant decrease in the D1 receptor abundance, suggesting a direct role of insulin on D1 receptor regulation. We conclude that hyperinsulinemia causes downregulation of D1 receptor function and lowering of plasma insulin levels leads to restoration of renal D1 receptor function.
我们之前报道过多巴胺 D1 样受体功能存在缺陷，这伴随着 D1 受体数量减少，以及在高胰岛素血症肥胖 Zucker 大鼠近端小管中多巴胺无法抑制钠钾 -ATP 酶和钠氢交换体。本研究旨在验证肥胖大鼠中多巴胺受体功能缺陷是高胰岛素血症所致这一假说。我们设计实验研究用罗格列酮治疗的肥胖 Zucker 大鼠的 D1 受体功能，因为罗格列酮可通过提高胰岛素敏感性来降低血浆胰岛素水平。一组未治疗的瘦鼠和肥胖鼠作为对照。与未治疗的肥胖大鼠相比，罗格列酮治疗（口服 10 mg/kg，4 周）可使血浆胰岛素、血糖和血压显著降低，同时使肾钠排泄增加。在从未治疗的瘦鼠分离得到的近端小管中，多巴胺可引起钠钾 -ATP 酶活性的浓度依赖性抑制，但在未治疗的肥胖大鼠中这种抑制作用不存在。在罗格列酮治疗的肥胖大鼠中，多巴胺对钠钾 -ATP 酶的抑制作用显著恢复。这伴随着治疗后肥胖大鼠近端小管膜中 D1 受体数量的完全恢复。在另一组实验中，用胰岛素处理培养基中的原代近端小管上皮细胞导致 D1 受体丰度显著降低，提示胰岛素在 D1 受体调节中起直接作用。我们得出结论，高胰岛素血症导致 D1 受体功能下调，而降低血浆胰岛素水平可导致肾 D1 受体功能恢复。
