Stretch reduces nephrin expression via an angiotensin II-AT1-dependent mechanism in human podocytes: effect of rosiglitazone
Stretch reduces nephrin expression via an angiotensin II-AT1-dependent mechanism in human podocytes: effect of rosiglitazone
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DOI：
10.1152/ajprenal.90423.2008
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发表时间：
2010-02-01
影响因子：
4.2
通讯作者：
Gruden, Gabriella
中科院分区：
文献类型：
--
作者：
Miceli, Ilaria;Burt, Davina;Gruden, Gabriella
Miceli I、Burt D、Tarabra E、Camussi G、Perin PC、Gruden G。拉伸通过人足细胞中血管紧张素 II-AT(1) 依赖性机制降低去氧肾上腺素表达：罗格列酮的作用。 Am J Physiol Renal Physiol 298：F381-F390，2010。首次发表于 2009 年 11 月 11 日； doi: 10.1152/ajprenal.90423.2008.-肾小球对蛋白质的通透性增加是糖尿病肾病 (DN) 的一个特征。狭缝隔膜是蛋白质过滤的主要限制位点，狭缝隔膜的关键成分去氧肾上腺素的损失已在人类和实验性 DN 中得到证实。全身性高血压和肾小球性高血压被认为在 DN 的发病机制中很重要。在存在或不存在坎地沙坦 (1 μM)、PD-123319 (1 μM) 和罗格列酮 (0.1 μM) 的情况下，使用应力单元（10% 伸长，60 个循环/分钟）通过机械变形对人永生化足细胞进行重复的拉伸-松弛循环。使用实时定量PCR、免疫印迹和免疫荧光评估去氧肾上腺素mRNA和蛋白表达，并评估AT(1)受体的蛋白表达和血管紧张素II分泌。拉伸导致去氧肾上腺素 mRNA 和蛋白质表达显着下降 50%。这种作用是由血管紧张素 II-AT(1) 机制介导的。事实上，足细胞拉伸会诱导血管紧张素 II 分泌和 AT(1) 受体过度表达，足细胞暴露于血管紧张素 II 会降低去氧肾上腺素蛋白的表达，而 AT-1 受体拮抗剂坎地沙坦和特异性抗血管紧张素 II 抗体都完全消除了拉伸诱导的去氧肾上腺素下调。与坎地沙坦类似，过氧化物酶体增殖物激活受体 (PPAR)-γ 激动剂罗格列酮也能抑制拉伸诱导的去氧肾上腺素下调，表明干扰拉伸诱导的血管紧张素 II-AT(1) 受体系统激活。因此，罗格列酮不会改变拉伸诱导的血管紧张素 II 分泌，但它可以防止拉伸引起的 AT(1) 上调。这些结果表明血流动力学应激在去氧肾上腺素表达丧失中发挥作用，并暗示 PPAR-γ 激动剂在预防这种丧失中的作用。
Miceli I, Burt D, Tarabra E, Camussi G, Perin PC, Gruden G. Stretch reduces nephrin expression via an angiotensin II-AT(1)-dependent mechanism in human podocytes: effect of rosiglitazone. Am J Physiol Renal Physiol 298: F381-F390, 2010. First published November 11, 2009; doi: 10.1152/ajprenal.90423.2008.-Increased glomerular permeability to proteins is a characteristic feature of diabetic nephropathy (DN). The slit diaphragm is the major restriction site to protein filtration, and the loss of nephrin, a key component of the slit diaphragm, has been demonstrated in both human and experimental DN. Both systemic and glomerular hypertension are believed to be important in the pathogenesis of DN. Human immortalized podocytes were subjected to repeated stretch-relaxation cycles by mechanical deformation with the use of a stress unit (10% elongation, 60 cycles/min) in the presence or absence of candesartan (1 mu M), PD-123319 (1 mu M), and rosiglitazone (0.1 mu M). Nephrin mRNA and protein expression were assessed using quantitative real-time PCR, immunoblotting, and immunofluorescence, and the protein expression of AT(1) receptor and angiotensin II secretion were evaluated. Exposure to stretch induced a significant similar to 50% decrease in both nephrin mRNA and protein expression. This effect was mediated by an angiotensin II-AT(1) mechanism. Indeed, podocyte stretching induced both angiotensin II secretion and AT(1) receptor overexpression, podocyte exposure to angiotensin II reduced nephrin protein expression, and both the AT-1 receptor antagonist candesartan and a specific anti-angiotensin II antibody completely abolished stretch-induced nephrin downregulation. Similar to candesartan, the peroxisome proliferator-activated receptor (PPAR)-gamma agonist, rosiglitazone, also inhibited stretch-induced nephrin downregulation, suggesting interference with stretchinduced activation of the angiotensin II-AT(1) receptor system. Accordingly, rosiglitazone did not alter stretch-induced angiotensin II secretion, but it prevented AT(1) upregulation in response to stretch. These results suggest a role for hemodynamic stress in loss of nephrin expression and allude to a role of PPAR-gamma agonists in the prevention of this loss.