Butyrate alleviates diabetic kidney disease by mediating the miR-7a-5p/P311/TGF-β1 pathway
Butyrate alleviates diabetic kidney disease by mediating the miR-7a-5p/P311/TGF-β1 pathway
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丁酸盐通过介导 miR-7a-5p/P311/TGF-β1 通路缓解糖尿病肾病
DOI：
10.1096/fj.202000431r
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发表时间：
2020-06-15
期刊：
影响因子：
4.8
通讯作者：
Yuan, Wei-Jie
中科院分区：
文献类型：
--
作者：
Du, Yi;Yang, Yi-Tong;Yuan, Wei-Jie
已有报道丁酸盐对糖尿病肾病(DKD)具有保护作用，但其作用机制尚不清楚。转化生长因子-β1(转化生长因子-β1)是触发肝纤维化信号转导通路的初始因子。P311是一种RNA结合蛋白，可以在多种细胞类型中刺激转化生长因子-β1的翻译。在我们的研究中，我们发现补充丁酸盐可以减轻db/db小鼠肾脏的纤维化，抑制转化生长因子-β1和P311的表达，以及高糖诱导的SV40-MES-13细胞。P311的过表达抵消了丁酸对SV40-MES-13细胞转化生长因子-β1的抑制作用。为了阐明丁酸对P311的调控机制，我们对SV40-MES-13细胞的microRNAs(MiRNAs)进行了测序。我们发现在HG诱导的SV40-MES-13细胞和db/db小鼠肾脏中miR-7a-5p的表达显著降低，而丁酸则逆转了这种变化。此外，miR-7a-5p可特异性靶向P311‘S基因3’端非编码区，并抑制P311在SV40-MES-13细胞中的表达。给予miR-7a-5p抑制剂可阻断丁酸对P311和TGF-β1的抑制作用。将miR-7a-5p异构体引入db/db小鼠可减轻肾纤维化，抑制P311和TGF-β1的表达。
It has been reported that butyrate played an protect role in diabetic kidney disease (DKD) while the mechanism was still not clear. Transforming growth factor-beta 1 (TGF-beta 1) is the initial factor which triggers the profibrotic signaling cascades. P311 is an RNA-binding protein, which could stimulate TGF-beta 1 translation in several cell types. In our study, we found that supplementary of butyrate alleviated fibrosis and suppressed the expression of TGF-beta 1 and P311 in the kidney of db/db mice as well as high glucose (HG)-induced SV40-MES-13 cells. Overexpression of P311 offset the inhibition of butyrate on TGF-beta 1 in SV40-MES-13 cells. To make clear the mechanism of butyrate in regulating P311, microRNAs (miRNAs) of the SV40-MES-13 cells were sequenced. We found that miR-7a-5p was significantly decreased in the HG-induced SV40-MES-13 cells and the kidney of db/db mice, while giving butyrate reversed this change. Besides, miR-7a-5p could specifically target the 3' UTR of P311's mRNA and suppressed the expression of P311 in the SV40-MES-13 cells. Giving miR-7a-5p inhibitor blocked the inhibition of butyrate on P311 and TGF-beta 1. Introducing the miR-7a-5p agomir into db/db mice alleviated renal fibrosis and inhibit the expression of P311 and TGF-beta 1. In conclusion, butyrate alleviated DKD by mediating the miR-7a-5p/P311/TGF-beta 1 pathway.