Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression
Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression
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系膜细胞中钙池操纵的 Ca2 通道抑制基质蛋白表达
DOI：
10.1681/asn.2014090853
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发表时间：
2015-11-01
影响因子：
13.6
通讯作者：
Ma, Rong
中科院分区：
文献类型：
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作者：
Wu, Peiwen;Wang, Yanxia;Ma, Rong
来源于肾小球系膜细胞的细胞外基质的积累是糖尿病肾病的早期特征。Ca2+信号介导的存储操作Ca2+通道调节蛋白生产在多种细胞类型。本研究的目的是确定系膜细胞中储存操作的Ca2+通道对细胞外基质蛋白表达的影响。在培养的人系膜细胞中，thapsigargin激活储存操作的Ca2+通道显著降低纤维连接蛋白表达和胶原IV mRNA表达，并呈剂量依赖性。相反，2-氨基乙基二苯硼酸盐对通道的抑制显著增加了纤维连接蛋白和胶原蛋白IV的表达。同样，基质相互作用分子1的过表达减少，但钙释放激活钙通道蛋白1 （Orai1）的敲低增加了纤维连接蛋白的表达。此外，2-氨基乙基二苯硼酸盐显著增强血管紧张素ii诱导的纤维连接蛋白表达，而thapsigargin则消除了高葡萄糖和tgf - β 1刺激的基质蛋白表达。使用靶向纳米颗粒siRNA递送系统在体内敲除小鼠系膜细胞中的Orai1，导致肾小球纤维连接蛋白和胶原IV的表达增加，与对照组相比，小鼠显示出明显的系膜扩张。同样，在体内用重组腺相关病毒编码的shRNA敲低肾系膜细胞基质相互作用分子1可显著增加肾皮质胶原IV蛋白的表达，导致大鼠肾系膜扩张。这些结果表明，肾系膜细胞中储存操作的Ca2+通道负调控细胞外基质蛋白的表达，这可能是糖尿病的内源性肾保护机制。
Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca2+ signals mediated by store-operated Ca2+ channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca2+ channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store-operated Ca2+ channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium release-activated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2-aminoethyl diphenylborinate significantly augmented angiotensin II-induced fibronectin protein expression, whereas thapsigargin abrogated high glucose- and TGF-beta 1-stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno-associated virus-encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store-operated Ca2+ channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes.