Nephrology Research and Development Unit, Faculty of Medicine & Hospital S. João EPE, Porto, Portugal.
Nephrol Dial Transplant. 2010 Sep;25(9):2945-53. doi: 10.1093/ndt/gfq150. Epub 2010 Mar 25.
It was demonstrated in streptozotocin (STZ)-induced diabetic rats that the D(1) receptor agonist failed to promote sodium excretion as a result of reduced renal D(1) receptor expression and decreased receptor G protein coupling. The present study examined the influence of glycaemic control with insulin on the renal D(1) receptor dysfunction in STZ-induced type 1 diabetes.
Renal function, blood pressure, the natriuretic response to 5% volume expansion (VE) and the effects of the D(1) receptor agonist fenoldopam on natriuresis and on Na(+)/K(+)-ATPase activity in renal tubules were evaluated in uninephrectomized and sham-operated Wistar rats treated with STZ and compared with controls and STZ-treated rats made euglycaemic with insulin. D(1) receptor immunohistochemistry and protein abundance by western blot were also determined in all groups.
Treatment of sham and uninephrectomized rats with STZ caused a 4-fold increase in glucose plasma levels compared to controls and euglycaemic diabetic rats. A blunted natriuretic response to VE was observed in both sham and uninephrectomized hyperglycaemic diabetic rats, and this was accompanied by failure of fenoldopam to increase natriuresis and to inhibit renal Na(+)/K(+)-ATPase activity. In contrast, in both sham and uninephrectomized euglycaemic diabetic rats, the natriuretic response to VE, the fenoldopam-induced natriuresis and the accompanied inhibition of Na(+)/K(+)-ATPase activity were similar to those of the corresponding controls. D(1) receptor immunodetection and protein abundance were reduced in hyperglycaemic diabetic rats, but not in euglycaemic diabetic animals.
We conclude that the renal expression and natriuretic response to D(1) receptor activation is compromised in both sham and uninephrectomized rats with STZ-induced diabetes. These abnormalities were prevented by lowering glucose blood levels with insulin, thus providing evidence for the involvement of hyperglycaemia in the disturbances that underlie the compromised dopamine-sensitive natriuresis and increase of blood pressure in type 1 diabetes.
在链脲佐菌素（STZ）诱导的糖尿病大鼠中，D1 受体激动剂未能促进钠排泄，这是由于肾脏 D1 受体表达减少和受体 G 蛋白偶联减少所致。本研究探讨了胰岛素对 STZ 诱导的 1 型糖尿病中肾脏 D1 受体功能障碍的影响。
在接受 STZ 治疗的单侧肾切除和假手术 Wistar 大鼠中评估肾功能、血压、5%容量扩张（VE）的利钠反应以及 D1 受体激动剂非诺多泮对利钠作用和肾小管中 Na+/K+-ATP 酶活性的影响，并与对照组和胰岛素使血糖正常的 STZ 治疗组进行比较。还通过免疫组织化学和 Western blot 确定了所有组中的 D1 受体免疫组化和蛋白丰度。
与对照组和血糖正常的糖尿病大鼠相比，接受 STZ 治疗的假手术和单侧肾切除大鼠的血糖水平升高了 4 倍。在 sham 和 uninephrectomized 高血糖糖尿病大鼠中，VE 的利钠反应减弱，这伴随着非诺多泮不能增加利钠作用和抑制肾 Na+/K+-ATP 酶活性。相比之下，在 sham 和 uninephrectomized 血糖正常的糖尿病大鼠中，VE 的利钠反应、非诺多泮诱导的利钠作用以及伴随的 Na+/K+-ATP 酶活性抑制与相应的对照组相似。D1 受体免疫检测和蛋白丰度在高血糖糖尿病大鼠中减少，但在血糖正常的糖尿病动物中没有减少。
我们得出结论，STZ 诱导的糖尿病 sham 和 uninephrectomized 大鼠的肾脏表达和 D1 受体激活的利钠反应受损。通过胰岛素降低血糖水平可预防这些异常，从而为高血糖参与 1 型糖尿病中受损的多巴胺敏感利钠作用和血压升高提供了证据。
