Wehbi G J, Zimpelmann J, Carey R M, Levine D Z, Burns K D
Department of Cellular and Molecular Medicine, Division of Nephrology, The Kidney Research Centre, Ottawa Hospital Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
Am J Physiol Renal Physiol. 2001 Feb;280(2):F254-65. doi: 10.1152/ajprenal.2001.280.2.F254.
The interaction of ANG II with intrarenal AT1 receptors has been implicated in the progression of diabetic nephropathy, but the role of intrarenal AT2 receptors is unknown. The present studies determined the effect of early diabetes on components of the glomerular renin-angiotensin system and on expression of kidney AT2 receptors. Three groups of rats were studied after 2 wk: 1) control (C), 2) streptozotocin (STZ)-induced diabetic (D), and 3) STZ-induced diabetic with insulin implant (D+I), to maintain normoglycemia. By competitive RT-PCR, early diabetes had no significant effect on glomerular mRNA expression for renin, angiotensinogen, or angiotensin-converting enzyme (ACE). In isolated glomeruli, nonglycosylated (41-kDa) AT1 receptor protein expression (AT1A and AT1B) was increased in D rats, with no change in glycosylated (53-kDa) AT1 receptor protein or in AT1 receptor mRNA. By contrast, STZ diabetes caused a significant decrease in glomerular AT2 receptor protein expression (47.0 +/- 6.5% of C; P < 0.001; n = 6), with partial reversal in D+I rats. In normal rat kidney, AT2 receptor immunostaining was localized to glomerular endothelial cells and tubular epithelial cells in the cortex, interstitial, and tubular cells in the outer medulla, and inner medullary collecting duct cells. STZ diabetes caused a significant decrease in AT2 receptor immunostaining in all kidney regions, an effect partially reversed in D+I rats. In summary, early diabetes has no effect on glomerular mRNA expression for renin, angiotensinogen, or ACE. AT2 receptors are present in glomeruli and are downregulated in early diabetes, as are all kidney AT2 receptors. Our data suggest that alterations in the balance of kidney AT1 and AT2 receptor expression may contribute to ANG II-mediated glomerular injury in progressive diabetic nephropathy.
血管紧张素II（ANG II）与肾内血管紧张素II 1型（AT1）受体的相互作用被认为与糖尿病肾病的进展有关，但肾内血管紧张素II 2型（AT2）受体的作用尚不清楚。本研究确定了早期糖尿病对肾小球肾素-血管紧张素系统成分及肾脏AT2受体表达的影响。对三组大鼠进行了为期2周的研究：1）对照组（C），2）链脲佐菌素（STZ）诱导的糖尿病组（D），3）STZ诱导的糖尿病并植入胰岛素组（D+I），以维持血糖正常。通过竞争性逆转录-聚合酶链反应（RT-PCR），早期糖尿病对肾小球肾素、血管紧张素原或血管紧张素转换酶（ACE）的mRNA表达无显著影响。在分离的肾小球中，非糖基化（41 kDa）的AT1受体蛋白表达（AT1A和AT1B）在D组大鼠中增加，糖基化（53 kDa）的AT1受体蛋白或AT1受体mRNA无变化。相比之下，STZ糖尿病导致肾小球AT2受体蛋白表达显著降低（为C组的47.0±6.5%；P<0.001；n=6），在D+I组大鼠中部分逆转。在正常大鼠肾脏中，AT2受体免疫染色定位于皮质的肾小球内皮细胞和肾小管上皮细胞、外髓质的间质和肾小管细胞以及内髓质集合管细胞。STZ糖尿病导致所有肾区的AT2受体免疫染色显著降低，在D+I组大鼠中这种作用部分逆转。总之，早期糖尿病对肾小球肾素、血管紧张素原或ACE的mRNA表达无影响。AT2受体存在于肾小球中，在早期糖尿病中下调，所有肾脏AT2受体均如此。我们的数据表明，肾脏AT1和AT2受体表达平衡的改变可能导致进行性糖尿病肾病中ANG II介导的肾小球损伤。
