TY - JOUR
T1 - Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis
AU - Wang, Bo
AU - Komers, Radko
AU - Carew, Rosemarie
AU - Winbanks, Catherine E.
AU - Xu, Bei
AU - Herman-Edelstein, Michal
AU - Koh, Philip
AU - Thomas, Merlin
AU - Jandeleit-Dahm, Karin
AU - Gregorevic, Paul
AU - Cooper, Mark E.
AU - Kantharidis, Phillip
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2011010055
DO - 10.1681/ASN.2011010055
M3 - Article
C2 - 22095944
AN - SCOPUS:84863115180
SN - 1046-6673
VL - 23
SP - 252
EP - 265
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 2
ER -