MiR‐29 mediates TGFβ1‐induced extracellular matrix synthesis through activation of PI3K‐AKT pathway in human lung fibroblasts

Abstract

TGFβ1 is very important in the synthesis and degradation of extracellular matrix, and also in the mediation of human lung fibroblasts proliferation, and miR-29 plays an important role in this process. To explore the interactions of miR-29 family members and TGFβ1, the effects of transforming growth factor TGFβ1 on the expression of miR-29 and whether miR-29 is involved in pro-survival signaling pathways mediated by TGFβ1 were examined in human lung fibroblasts. Treatment of the human embryonic lung fibroblast cell line IMR90 with TGFβ1 caused a decrease in expression of miR-29a/b/c by real-time PCR analysis. TGFβ1 stimulation increased cell proliferation, colony formation and up-regulated expression of COL1A1; transfecting with miR-29a/b/c mimics reverse TGFβ1-induced phenotype changes in IMR90 cells. Western blot analyses showed that TGFβ1 treatment unchanged total protein expression levels of PI3K or AKT, but the expression levels of p-PI3K, p-AKT, and COL1A1 were increased; and miR-19a/b/c mimics interfering blocked phosphorylation of PI3K or AKT and decreased expression of COL1A1 after TGFβ1 treatment. The results indicate that TGFβ1 beta uses the PI3k-Akt pathway in these embryonic fibroblasts and miR29 blocks this activation pathway. It indicates a novel biological function of the PI3K-Akt pathway in IMR90. Elevated expression of miR-29 may play an important role in the pathogenesis of diseases related to fibrogenic reactions in human lung fibroblasts.

Fibrotic extracellular matrix activates a profibrotic positive feedback loop

“…In fact, a recent study has shown that miR-29 gene transfer into the lungs of mice with bleomycin-induced lung fibrosis can arrest -but not reverse -the progression of fibrosis (47). In addition, downregulation of miR-29 is known to activate the synthesis of ECM products by lung fibroblasts (48). Together with our observation that miR29c is downregulated by fibrotic ECM, these findings support a causal link between fibrotic ECM, downregulation of fibroblast miR-29, and the progression of fibrosis.…”

Role of the microRNA-29 family in fibrotic skin diseases

“…Various studies have independently demonstrated that the miR-29 family targets >20 ECM-associated genes, including collagen, elastin and integrin B1; therefore, the miR-29 family is a major target of this miRNA family (22,24). miR-29 family members are actively involved in the fibrotic processes of various types of tissue, such as liver (25,36,37), pulmonary (19,38,39), cardiac (40,41) and renal (24,42), as well as in systemic sclerosis (23,(43)(44)(45), trabecular meshwork (9) and bone remodelling (20,21,46). Downregulation of different miR-29 family members has been reported in the liver (25,37,47,48), lungs (19,49), heart (25,41), kidneys (50,51) and skin (23) (Fig.…”

Transforming growth factor-β1 increases lysyl oxidase expression by downregulating MIR29A in human granulosa lutein cells

“…Clinical data have shown that MIR29A levels are reduced in the serum of PCOS patients (Ding et al 2015). Interestingly, emerging results from in vitro studies have demonstrated that the expression of MIR29A is downregulated by TGFB1 in many cell types, including fibroblasts and tubular epithelial cells (Maurer et al 2010, Qin et al 2011, Wang et al 2012, Yang et al 2013. Given that PCOS patients have higher expression levels of TGFB1 and LOX as well as lower expression levels of MIR29A, we hypothesized that TGFB1 increases the expression of LOX by downregulating MIR29A in human granulosa cells.…”