| First Author | Castro NE | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 42 | Pages | 29001-13 |
| PubMed ID | 25204661 | Mgi Jnum | J:218809 |
| Mgi Id | MGI:5618408 | Doi | 10.1074/jbc.M114.600783 |
| Citation | Castro NE, et al. (2014) Transforming growth factor beta1 (TGF-beta1) enhances expression of profibrotic genes through a novel signaling cascade and microRNAs in renal mesangial cells. J Biol Chem 289(42):29001-13 |
| abstractText | Increased expression of transforming growth factor-beta1 (TGF-beta1) in glomerular mesangial cells (MC) augments extracellular matrix accumulation and hypertrophy during the progression of diabetic nephropathy (DN), a debilitating renal complication of diabetes. MicroRNAs (miRNAs) play key roles in the pathogenesis of DN by modulating the actions of TGF-beta1 to enhance the expression of profibrotic genes like collagen. In this study, we found a significant decrease in the expression of miR-130b in mouse MC treated with TGF-beta1. In parallel, there was a down-regulation in miR-130b host gene 2610318N02RIK (RIK), suggesting host gene-dependent expression of this miRNA. TGF-beta receptor 1 (TGF-betaR1) was identified as a target of miR-130b. Interestingly, the RIK promoter contains three NF-Y binding sites and was regulated by NF-YC. Furthermore, NF-YC expression was inhibited by TGF-beta1, suggesting that a signaling cascade, involving TGF-beta1-induced decreases in NF-YC, RIK, and miR-130b, may up-regulate TGF-betaR1 to augment expression of TGF-beta1 target fibrotic genes. miR-130b was down-regulated, whereas TGF-betaR1, as well as the profibrotic genes collagen type IV alpha 1 (Col4a1), Col12a1, CTGF, and PAI-1 were up-regulated not only in mouse MC treated with TGF-beta1 but also in the glomeruli of streptozotocin-injected diabetic mice, supporting in vivo relevance. Together, these results demonstrate a novel miRNA- and host gene-mediated amplifying cascade initiated by TGF-beta1 that results in the up-regulation of profibrotic factors, such as TGF-betaR1 and collagens associated with the progression of DN. |
