张力素
PTEN公司
癌症研究
生物
PI3K/AKT/mTOR通路
十指瘫痪
磷酸化
蛋白激酶B
细胞生物学
糖尿病肾病
纤维化
磷酸酶
信号转导
内分泌学
内科学
肾
转录因子
医学
生物化学
基因
增强子
作者
Aaron McClelland,Michal Herman‐Edelstein,Radko Komers,Jay C. Jha,Catherine E. Winbanks,Shinji Hagiwara,Paul Gregorevic,Phillip Kantharidis,Mark E. Cooper
出处
期刊:Clinical Science
[Portland Press]
日期:2015-09-29
卷期号:129 (12): 1237-1249
被引量:203
摘要
The cytokine transforming growth factor (TGF)-β1 plays a central role in diabetic nephropathy (DN) with data implicating the miRNA (miR) miR-21 as a key modulator of its prosclerotic actions. In the present study, we demonstrate data indicating that miR-21 up-regulation positively correlates with the severity of fibrosis and rate of decline in renal function in human DN. Furthermore, concomitant analyses of various models of fibrotic renal disease and experimental DN, confirm tubular miR-21 up-regulation. The fibrotic changes associated with increased miR-21 levels are proposed to include the regulation of TGF-β1-mediated mothers against decapentaplegic homolog 3 (SMAD3)- and phosphoinositide 3-kinase (PI3K)-dependent signalling pathways via co-ordinated repression of mothers against decapentaplegic homolog 7 (SMAD7) and phosphatase and tensin homologue (PTEN) respectively. This represents a previously uncharacterized interaction axis between miR-21 and PTEN–SMAD7. Targeting of these proteins by miR-21 resulted in de-repression of the respective pathways as reflected by increases in SMAD3 and V-Akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation. Many of the changes typically induced by TGF-β1, including phosphorylation of signalling mediators, were further enhanced by miR-21. Collectively, these data present a unified model for a key role for miR-21 in the regulation of renal tubular extracellular matrix (ECM) synthesis and accumulation and provide important insights into the molecular pathways implicated in the progression of DN.
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