MicroRNA-133a-Dependent Inhibition of Proximal Tubule Angiotensinogen by Renal TNF (Tumor Necrosis Factor).
MicroRNA-133a-Dependent Inhibition of Proximal Tubule Angiotensinogen by Renal TNF (Tumor Necrosis Factor).
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DOI：
10.1161/hypertensionaha.120.15435
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Ferreri NR
中科院分区：
文献类型：
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作者：
Hao S;Salzo J;Zhao H;Hao M;Darzynkiewicz Z;Ferreri NR
我们发现，在低盐（LS）条件下，肾内抑制TNF的产生会增加肾皮质AGT mRNA和蛋白的表达。小鼠肾内注射重组TNF可降低摄入LS小鼠体内AGT的升高。此外，在摄入LS的小鼠中，同时接受肾内注射特异性沉默肾脏TNF （U6-TNF-ex4）的慢病毒构建体，AGT mRNA和蛋白的表达分别增加了约6倍和2倍。正常盐（NS）和高盐（HS）条件下TNF的沉默也导致AGT表达增加。由于肾TNF生成在LS下减少，在HS下增加，数据表明在这些条件下TNF生成的改变调节了AGT表达的程度。我们还验证了TNF通过涉及miR-133a的机制抑制肾内AGT表达的假设。在给予LS的小鼠中，miR-133a的表达降低，在HS的作用下，miR-133a的表达升高，持续7天。TNF的肾内沉默逆转了HS对mir -133a依赖性AGT表达的影响。相反，肾内给药TNF增加了miR-133a在肾脏中的表达。总的来说，这些数据表明miR-133a是一种盐敏感的miRNA，可以抑制肾脏中的AGT，并被TNF增加。在TNF沉默后观察到的HS诱导的血压升高在肾内给予miR-133a后显着降低，这表明肾脏中TNF限制HS血压反应的内在作用包括miR-133a的增加，其抑制AGT的表达。
We showed that intrarenal suppression of TNF production under low salt (LS) conditions increases renal cortical AGT mRNA and protein expression. Intrarenal injection of murine recombinant TNF attenuated increases of AGT in mice ingesting LS. Moreover, AGT mRNA and protein expression increased approximately 6-fold and 2-fold, respectively, in mice ingesting LS that also received an intrarenal injection of a lentivirus construct that specifically silenced TNF in the kidney (U6-TNF-ex4). Silencing of TNF under normal salt (NS) and high salt (HS) conditions also resulted in increased AGT expression. Since renal TNF production decreases in response to LS and increases in response to HS, the data suggest that alterations in TNF production under these conditions modulates the degree of AGT expression. We also tested the hypothesis that TNF inhibits intrarenal AGT expression by a mechanism involving miR-133a. Expression of miR-133a decreased in mice given LS and increased in response to HS for 7 days. Intrarenal silencing of TNF reversed the effects of HS on miR-133a-dependent AGT expression. In contrast, intrarenal TNF administration increased miR-133a expression in the kidney. Collectively, the data suggest that miR-133a is a salt-sensitive miRNA that inhibits AGT in the kidney and is increased by TNF. The HS-induced increase in blood pressure observed following silencing of TNF was markedly reduced upon intrarenal administration of miR-133a suggesting that intrinsic effects of TNF in the kidney to limit the blood pressure response to HS include an increase in miR-133a, which suppresses AGT expression.