McClelland Aaron D, Herman-Edelstein Michal, Komers Radko, Jha Jay C, Winbanks Catherine E, Hagiwara Shinji, Gregorevic Paul, Kantharidis Phillip, Cooper Mark E
JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Domain, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia Department of Medicine, Central Clinical School, Monash University, 75 Commercial Road, Melbourne, VIC 3004, Australia.
Department of Nephrology & Hypertension, Rabin Medical Center, Petah Tikva, 4941492, Israel; Felsenstein Medical Research Institute, Rabin Medical Center, Petah Tikva, 49100, Israel; Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
Clin Sci (Lond). 2015 Dec;129(12):1237-49. doi: 10.1042/CS20150427. Epub 2015 Sep 28.
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.
细胞因子转化生长因子（TGF）-β1在糖尿病肾病（DN）中起核心作用，数据表明微小RNA（miR）-miR-21是其促纤维化作用的关键调节因子。在本研究中，我们展示的数据表明，miR-21上调与人类DN中纤维化的严重程度和肾功能下降速率呈正相关。此外，对各种纤维化肾病模型和实验性DN的同步分析证实了肾小管miR-21上调。与miR-21水平升高相关的纤维化变化被认为包括通过分别协同抑制抗五聚体蛋白同源物7（SMAD7）和磷酸酶及张力蛋白同源物（PTEN）来调节TGF-β1介导的抗五聚体蛋白同源物3（SMAD3）和磷脂酰肌醇3激酶（PI3K）依赖性信号通路。这代表了miR-21与PTEN-SMAD7之间以前未被描述的相互作用轴。miR-21对这些蛋白质的靶向作用导致相应信号通路的去抑制，这表现为SMAD3和V-Akt小鼠胸腺瘤病毒癌基因同源物1（AKT）磷酸化增加。许多通常由TGF-β1诱导的变化，包括信号介质的磷酸化，都被miR-21进一步增强。总体而言，这些数据为miR-21在调节肾小管细胞外基质（ECM）合成和积累中的关键作用提供了一个统一模型，并为DN进展所涉及的分子途径提供了重要见解。
