Activation of a local renin angiotensin system in podocytes by glucose
Activation of a local renin angiotensin system in podocytes by glucose
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DOI：
10.1152/ajprenal.00266.2007
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发表时间：
2008-04-01
影响因子：
4.2
通讯作者：
Shankland, Stuart J.
中科院分区：
文献类型：
--
作者：
Durvasula, Raghu V.;Shankland, Stuart J.
ANG II 是糖尿病肾病的关键介质。 ANG II 的药物抑制可减缓疾病进展，超出了单独通过降压作用所能预测的范围，这表明 ANG II 非血流动力学途径在介导疾病中的重要性。足细胞损伤和丢失是糖尿病肾病的主要特征。越来越多的证据表明，足细胞是糖尿病肾病中 ANG II 介导的信号传导的直接目标。我们测试了高葡萄糖导致足细胞中局部血管紧张素系统激活的假设，并描绘了所涉及的潜在途径。将培养的足细胞暴露于标准葡萄糖 (5 mM)、高葡萄糖 (40 mM) 或甘露醇作为渗透压控制。在存在或不存在血管紧张素转换酶（卡托普利）、糜酶（糜抑素）和肾素（阿利吉仑）活性抑制剂的情况下测量细胞裂解物中的 ANG II 水平。测定了葡萄糖对肾素和血管紧张素亚型1受体表达和蛋白质水平的影响。暴露于高葡萄糖会导致肾素活性增加介导的 ANG II 水平增加 2.1 倍，因为暴露于高葡萄糖会增加肾素水平，并且与阿利吉仑预孵育会消除葡萄糖诱导的 ANG II 产生。通过显示实验性糖尿病肾病早期足细胞分布中肾小球肾素原受体的上调，证明了与体内环境的相关性。此外，通过免疫荧光和蛋白质印迹检测，高葡萄糖增加了血管紧张素亚型 1 受体水平。总而言之，高血糖引起的局部肾素血管紧张素系统的激活可能会促进糖尿病肾病中足细胞的进行性损伤和丧失。
ANG II is a critical mediator of diabetic nephropathy. Pharmacologic inhibition of ANG II slows disease progression beyond what could be predicted by the blood pressure lowering effects alone, suggesting the importance of nonhemodynamic pathways of ANG II in mediating disease. Podocyte injury and loss are cardinal features of diabetic nephropathy. Mounting evidence suggests that the podocyte is a direct target of ANG II-mediated signaling in diabetic renal disease. We have tested the hypothesis that high glucose leads to the activation of a local angiotensin system in podocytes and delineated the underlying pathways involved. Cultured podocytes were exposed to standard glucose (5 mM), high glucose (40 mM), or mannitol as an osmotic control. ANG II levels in cell lysates were measured in the presence or absence of inhibitors of angiotensin-converting enzyme (captopril), chymase (chymostatin), and renin (aliskiren) activity. The effects of glucose on renin and angiotensin subtype 1 receptor expression and protein levels were determined. Exposure to high glucose resulted in a 2.1-fold increase ANG II levels mediated through increased renin activity, as exposure to high glucose increased renin levels and preincubation with Aliskiren abrogated glucose-induced ANG II production. Relevance to the in vivo setting was demonstrated by showing glomerular upregulation of the prorenin receptor in a podocyte distribution early in the course of experimental diabetic nephropathy. Furthermore, high glucose increased angiotensin subtype 1 receptor levels by immunofluorescence and Western blot. Taken together, the resultant activation of a local renin angiotensin system by high glucose may promote progressive podocyte injury and loss in diabetic nephropathy.