RENAL RENIN-ANGIOTENSIN SYSTEM IN DIABETES - FUNCTIONAL, IMMUNOHISTOCHEMICAL, AND MOLECULAR BIOLOGICAL CORRELATIONS
RENAL RENIN-ANGIOTENSIN SYSTEM IN DIABETES - FUNCTIONAL, IMMUNOHISTOCHEMICAL, AND MOLECULAR BIOLOGICAL CORRELATIONS
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DOI：
10.1152/ajprenal.1993.265.4.f477
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发表时间：
1993-10-01
影响因子：
--
通讯作者：
INGELFINGER, JR
中科院分区：
文献类型：
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作者：
ANDERSON, S;JUNG, FF;INGELFINGER, JR
最近的证据表明肾素-血管紧张素系统（RAS）在糖尿病肾小球损伤的发病机制中发挥作用。为了进一步探索糖尿病中的 RAS，在非糖尿病对照大鼠和中度高血糖糖尿病 (DM) 大鼠中进行了研究。在 DM 大鼠中，使用特异性血管紧张素 II (ANG II) 受体拮抗剂氯沙坦进行急性和慢性治疗均不会影响肾小球过度滤过或过度灌注，但选择性地使肾小球毛细血管液压和超滤系数正常化。为了确定肾内血流动力学对 RAS 抑制反应的基础，我们进行了生化、分子生物学和免疫组织化学研究来评估内源性 RAS 活性。 DM 大鼠的血浆肾素浓度和血清血管紧张素转换酶 (ACE) 活性值正常。相反，DM 大鼠肾内肾素蛋白含量以及肾素和血管紧张素原 mRNA 增加，表明肾内 RAS 激活不成比例。 DM 大鼠中总肾 ACE 活性显着降低，但免疫组织化学研究表明 ACE 在糖尿病肾脏中重新分布。近端肾小管 ACE 活性降低，但肾小球和肾血管系统中 ACE 免疫染色强度增强。总之，这些观察结果表明，最有可能调节血流动力学功能的部位（肾小球和脉管系统）中 RAS 活性增加，这可能解释了药物阻断 ANG II 形成和/或作用的显着反应。
Recent evidence indicates a role for the renin-angiotensin system (RAS) in the pathogenesis of glomerular injury in diabetes. To further explore the RAS in diabetes, studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic (DM) rats. In DM rats, both acute and chronic therapy with the specific angiotensin II (ANG II) receptor antagonist losartan did not affect glomerular hyperfiltration or hyperperfusion but selectively normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. To determine the basis of intrarenal hemodynamic responsiveness to RAS inhibition, we conducted biochemical, molecular biological, and immunohistochemical studies to assess endogenous RAS activity. Values for plasma renin concentration and serum angiotensin-converting enzyme (ACE) activity in DM rats were normal. In contrast, intrarenal renin protein content, and renin and angiotensinogen mRNAs, were increased in DM rats, suggesting disproportionate activation of the intrarenal RAS. Total renal ACE activity was significantly reduced in DM rats, but immunohistochemical studies indicated redistribution of ACE in the diabetic kidney. Proximal tubule ACE activity was reduced, but ACE immunostaining intensity was enhanced in glomeruli and renal vasculature. Together, these observations indicate increased RAS activity in those sites (glomeruli and vasculature) most likely to regulate hemodynamic function, potentially explaining the prominent responses to pharmacological blockade of ANG II formation and/or action.