| First Author | Park JT | Year | 2014 |
| Journal | Am J Physiol Renal Physiol | Volume | 307 |
| Issue | 12 | Pages | F1390-403 |
| PubMed ID | 25354942 | Mgi Jnum | J:216763 |
| Mgi Id | MGI:5609491 | Doi | 10.1152/ajprenal.00458.2014 |
| Citation | Park JT, et al. (2014) Repression of let-7 by transforming growth factor-beta1-induced Lin28 upregulates collagen expression in glomerular mesangial cells under diabetic conditions. Am J Physiol Renal Physiol 307(12):F1390-403 |
| abstractText | Accumulation of mesangial extracellular matrix (ECM) proteins such as collagen type 1-alpha2 (Col1a2) and collagen type 4-alpha1 (Col4a1) is a key feature of diabetic nephropathy (DN). Transforming growth factor (TGF)-beta1 plays important roles in ECM accumulation in DN, and evidence shows a mediatory role for microRNAs. In the present study, we found that microRNA let-7 family members (let-7b/c/d/g/i) were downregulated in TGF-beta-treated mouse mesangial cells (MMCs) along with upregulation of Col1a2 and Col4a1. Ectopic expression of let-7b in TGF-beta-treated MMCs attenuated Col1a2 and Col4a1 upregulation. Conversely, let-7b inhibitors increased Col1a2 and Col4a1 levels. Cotransfection of MMCs with mouse Col1a2 or Col4a1 3'-untranslated region luciferase constructs and let-7b inhibitors increased luciferase activity. However, constructs with let-7 target site mutations were unresponsive to TGF-beta. TGF-beta-induced 3'-untranslated region activity was attenuated by let-7b mimics, suggesting that Col1a2 and Col4a1 are direct targets of let-7b. In addition, Lin28b, a negative regulator of let-7 biogenesis, was upregulated in TGF-beta-treated MMCs. Luciferase assays showed that the Lin28b promoter containing the Smad-binding element (SBE) responded to TGF-beta, which was abolished in constructs without SBE. Chromatin immunoprecipitation assays showed TGF-beta-induced enrichment of Smad2/3 at the Lin28b promoter, together suggesting that Lin28b is transcriptionally induced by TGF-beta through SBE. Furthermore, let-7b levels were decreased, whereas Lin28b, Col1a2, and Col4a1 levels were increased, in glomeruli of diabetic mice compared with nondiabetic control mice, demonstrating the in vivo relevance of this Lin28/let-7/collagen axis. These results identify Lin28 as a new TGF-beta target gene and suggest a novel role for the Lin28/let-7 pathway in controlling TGF-beta-induced collagen accumulation in DN. |
