Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho.
Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho.
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DOI：
10.1016/j.kint.2016.09.039
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发表时间：
2017-04
影响因子：
19.6
通讯作者：
Huang CL
中科院分区：
文献类型：
--
作者：
Wu YL;Xie J;An SW;Oliver N;Barrezueta NX;Lin MH;Birnbaumer L;Huang CL
纤维化是一种夸张的组织修复形式，发生在严重损伤或重复损伤时，最终由于过度疤痕导致器官衰竭。钙离子通过TRPC6通道进入的增加与心脏和肾小球疾病的发病机制有关，但其在肾间质纤维化中的作用尚不清楚。我们通过在小鼠中缺失Trpc6来研究这一点，发现它可以减少单侧输尿管梗阻引起的间质纤维化，并且使输尿管梗阻肾脏中相对于野生型小鼠肾脏中增加的纤维化相关基因mRNA表达减弱。BTP2（一种已知能抑制几种TRPC通道功能的吡唑衍生物）也能改善野生型小鼠梗阻性肾纤维化和基因表达。BTP2抑制碳甾醇激活的HEK293细胞中TRPC3和TRPC6通道的活性。输尿管梗阻导致梗阻小鼠肾脏中TRPC3和TRPC6 mRNA表达比假手术小鼠增加10倍以上。Trpc3和Trpc6双敲除小鼠对阻塞性纤维化的保护程度与Trpc6敲除小鼠没有差异。Klotho是一种主要在肾脏中产生的膜和可溶性蛋白，已知可预防肾纤维化。可溶性klotho可显著减少野生型小鼠梗阻性肾纤维化，但在TRPC6基因敲除小鼠中无明显作用，表明klotho和TRPC6抑制作用在同一途径上保护梗阻性肾纤维化。因此，klotho和TRPC6可能是治疗肾纤维化的药理靶点。
Fibrosis is an exaggerated form of tissue repair that occurs with serious damage or repetitive injury and ultimately leads to organ failure due to the excessive scarring. Increased calcium ion entry through the TRPC6 channel has been associated with the pathogenesis of heart and glomerular diseases, but its role in renal interstitial fibrosis is unknown. We studied this by deletion of Trpc6 in mice and found it decrease unilateral ureteral obstruction-induced interstitial fibrosis, and blunted increased mRNA expression of fibrosis-related genes in the ureteral obstructed kidney relative to that in the kidney of wild-type mice. Administration of BTP2, a pyrazol derivative known to inhibit function of several TRPC channels, also ameliorated obstruction-induced renal fibrosis and gene expression in wild type mice. BTP2 inhibited carbachol-activated TRPC3 and TRPC6 channel activities in HEK293 cells. Ureteral obstruction caused over a 10-fold increase in mRNA expression for TRPC3 as well as TRPC6 in the kidneys of obstructed- relative to the sham-operated mice. The magnitude of protection against obstruction-induced fibrosis in Trpc3 and Trpc6 double knockout mice was not different from that in Trpc6-knockout mice. Klotho, a membrane and soluble protein predominantly produced in the kidney, is known to confer protection against renal fibrosis. Administration of soluble klotho significantly reduced obstruction-induced renal fibrosis in wild type mice, but not in Trpc6-knockout mice, indicating that klotho and TRPC6 inhibition act in the same pathway to protect against obstruction-induced renal fibrosis. Thus klotho and TRPC6 may be pharmacologic targets for treating renal fibrosis.