Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis

Bo Wang, Radko Komers, Rosemarie Carew, Catherine E. Winbanks, Bei Xu, Michal Herman-Edelstein, Philip Koh, Merlin Thomas, Karin Jandeleit-Dahm, Paul Gregorevic, Mark E. Cooper, Phillip Kantharidis

Research output: Contribution to journalArticle

324 Scopus citations

Abstract

Synthesis and deposition of extracellular matrix (ECM) within the glomerulus and interstitium characterizes renal fibrosis, but the mechanisms underlying this process are incompletely understood. The profibrotic cytokine TGF-β1 modulates the expression of certain microRNAs (miRNAs), suggesting that miRNAs may have a role in the pathogenesis of renal fibrosis. Here, we exposed proximal tubular cells, primary mesangial cells, and podocytes to TGF-β1 to examine its effect onmiRNAs and subsequent collagen synthesis. TGF-β1 reduced expression of the miR-29a/b/c/family, which targets collagen gene expression, and increased expression of ECMproteins. In both resting and TGF-β1-treated cells, ectopic expression of miR-29 repressed the expression of collagens I and IV at both the mRNA and protein levels by targeting the 3′untranslated region of these genes. Furthermore, we observed low levels of miR-29 in three models of renal fibrosis representing early and advanced stages of disease. Administration of the Rho-associated kinase inhibitor fasudil prevented renal fibrosis and restored expression of miR-29. Taken together, these data suggest that TGF-β1 inhibits expression of the miR-29 family, thereby promoting expression of ECM components. Pharmacologic modulation of these miRNAs may have therapeutic potential for progressive renal fibrosis.

Original languageEnglish (US)
Pages (from-to)252-265
Number of pages14
JournalJournal of the American Society of Nephrology
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2012

ASJC Scopus subject areas

  • Nephrology

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    Wang, B., Komers, R., Carew, R., Winbanks, C. E., Xu, B., Herman-Edelstein, M., Koh, P., Thomas, M., Jandeleit-Dahm, K., Gregorevic, P., Cooper, M. E., & Kantharidis, P. (2012). Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis. Journal of the American Society of Nephrology, 23(2), 252-265. https://doi.org/10.1681/ASN.2011010055