Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.
Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.
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DOI：
10.1038/s41598-017-04067-z
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发表时间：
2017-06-23
影响因子：
4.6
通讯作者：
Ma R
中科院分区：
文献类型：
--
作者：
Li W;Ding Y;Smedley C;Wang Y;Chaudhari S;Birnbaumer L;Ma R
本研究旨在确定TRPC6是否调节肾小球滤过率（GFR）和肾小球系膜细胞（MCs）的收缩功能。在清醒的TRPC6野生型和敲除小鼠，以及肾脏中TRPC6在体内敲除和未敲除的麻醉大鼠中评估GFR。我们发现TRPC6缺陷小鼠GFR显著升高，血清肌酐水平显著降低。同样，在肾脏中使用TRPC6特异性shRNA构建局部敲除TRPC6可显著减弱Ang ii诱导的大鼠GFR下降。此外，从TRPC6缺陷小鼠分离的原代MCs中，Ang ii刺激的收缩和Ca2+进入被显著抑制，并且通过重新引入TRPC6可以挽救Ca2+反应。此外，KB-R7943抑制Na+-Ca2+交换的反向模式显著降低了表达trpc6的MCs的Ca2+进入反应，但在trpc6敲除的MCs中没有。Ca2+进入反应在Na+游离溶液中也明显减弱。TRPC6和TRPC1的单敲低导致Ca2+进入的抑制与两者的双敲低相当。这些结果表明，TRPC6可能通过多种Ca2+信号通路调节MC收缩功能来调节GFR。
The present study was conducted to determine if TRPC6 regulates glomerular filtration rate (GFR) and the contractile function of glomerular mesangial cells (MCs). GFR was assessed in conscious TRPC6 wild type and knockout mice, and in anesthetized rats with and without in vivo knockdown of TRPC6 in kidneys. We found that GFR was significantly greater, and serum creatinine level was significantly lower in TRPC6 deficient mice. Consistently, local knockdown of TRPC6 in kidney using TRPC6 specific shRNA construct significantly attenuated Ang II-induced GFR decline in rats. Furthermore, Ang II-stimulated contraction and Ca2+ entry were significantly suppressed in primary MCs isolated from TRPC6 deficient mice, and the Ca2+ response could be rescued by re-introducing TRPC6. Moreover, inhibition of reverse mode of Na+-Ca2+ exchange by KB-R7943 significantly reduced Ca2+ entry response in TRPC6-expressing, but not in TRPC6-knocked down MCs. Ca2+ entry response was also significantly attenuated in Na+ free solution. Single knockdown of TRPC6 and TRPC1 resulted in a comparable suppression on Ca2+ entry with double knockdown of both. These results suggest that TRPC6 may regulate GFR by modulating MC contractile function through multiple Ca2+ signaling pathways.