Repression of let-7 by transforming growth factor-β1-induced Lin28 upregulates collagen expression in glomerular mesangial cells under diabetic conditions

Jung Tak Park, Mitsuo Kato, Linda Lanting, Nancy Castro, Bo Young Nam, Mei Wang, Shin Wook Kang, Rama Natarajan

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)


Accumulation of mesangial extracellular matrix (ECM) proteins such as collagen type 1-a2 (Col1a2) and collagen type 4-a1 (Col4a1) is a key feature of diabetic nephropathy (DN). Transforming growth factor (TGF)-ß1 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-ß-treated mouse mesangial cells (MMCs) along with upregulation of Col1a2 and Col4a1. Ectopic expression of let-7b in TGF-ß-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-ß. TGF-ß-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-ß-treated MMCs. Lu-ciferase assays showed that the Lin28b promoter containing the Smad-binding element (SBE) responded to TGF-ß, which was abolished in constructs without SBE. Chromatin immunoprecipitation assays showed TGF-ß-induced enrichment of Smad2/3 at the Lin28b promoter, together suggesting that Lin28b is transcriptionally induced by TGF-ß through SBE. Furthermore, let-7b levels were decreased, whereas Lin28b, Col1a2, and Col4a1 levels were increased, in glom-eruli 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-ß target gene and suggest a novel role for the Lin28/let-7 pathway in controlling TGF-ß-induced collagen accumulation in DN.

Original languageEnglish
Pages (from-to)F1390-F1403
JournalAmerican Journal of Physiology - Renal Physiology
Issue number12
Publication statusPublished - 2014 Dec 15

Bibliographical note

Publisher Copyright:
© 2014 the American Physiological Society.

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology


Dive into the research topics of 'Repression of let-7 by transforming growth factor-β1-induced Lin28 upregulates collagen expression in glomerular mesangial cells under diabetic conditions'. Together they form a unique fingerprint.

Cite this