Secreted fibroblast miR-34a induces tubular cell apoptosis in fibrotic kidney

Abstract

Tubular epithelial cell apoptosis contributes to tubulointerstitial fibrosis but its regulation remained unclear. Here, in fibrotic kidney induced by unilateral ureteral obstruction (UUO), we demonstrated that miR-34a was markedly up-regulated in tubulointerstitial spaces and microvesicles isolated from kidney. However, the increased miR-34a was not de novo synthesized by proximal tubular epithelial cells but by fibroblasts after incubated with TGF-β1. MiR-34a was markedly up-regulated in microvesicles isolated from cell culture media of TGF-β1 treated fibroblasts. These microvesicles acted as a vector for delivery of up-regulated miR-34a from fibroblasts to tubular cells. The fibroblast-derived miR-34a-containing microvesicles induced apoptosis of tubular cells. The exogenous miR-34a regulated tubular apoptosis by modulating the expression of anti-apoptotic protein Bcl-2. Moreover, injection of exogenous miR-34a-containing microvesicles enhanced tubular cell apoptosis in mice. This study suggests that secreted fibroblast miR-34a transported by microvesicles induces tubular cell apoptosis in obstructive kidney. This study provided a new mechanism concerning microvesicle-mediated fibroblast-to-tubular cell communication of miRNA in regulating tubular cell apoptosis, which might provide new therapeutic targets for renal tubulointerstitial fibrosis.

MicroRNA-214 acts as a potential oncogene in breast cancer by targeting the PTEN-PI3K/Akt signaling pathway

“…Taken together, these results suggest that miR-214 plays a critical role in the development and progression of breast cancer. miRNAs are endogenous, single-stranded, non-coding RNAs which are approximately 22 nucleotides in length and may suppress the post-transcriptional expression of target genes and are consequently involved in the regulation of various cellular processes, e.g., cell apoptosis, differentiation, development and metastasis (9,18,19). Growing evidence has reinforced the fact that miRNAs are frequently deregulated and aberrantly expressed in certain types of cancer, by acting as either tumor suppressors (9,20) or oncogenes (21, 22), and that they play a central role in carcinogenesis.…”

microRNA-214 enhances the invasion ability of breast cancer cells by targeting p53

“…Moreover, we demonstrated that the dysregulation of miR-214 is involved in the mechanisms of BC cell invasion by targeting p53. miRNAs are known to be endogenous single-stranded noncoding RNAs consisting of approximately 22 nucleotides, which can suppress the post-transcriptional expression of target genes and have been demonstrated to promote or suppress different cellular processes, e.g., cell apoptosis, differentiation, development, metastasis and invasion (31)(32)(33)(34)). An increasing number of studies have reinforced the notion that miRNAs are frequently deregulated and aberrantly expressed in certain types of cancer.…”

Emergence of miR-34a in radiation therapy

“…Moreover, overexpressing miR-34a levels increased the profibrogenic activity of TGF-β1 in cardiac fibroblast, whereas inhibition miR-34a levels weakened the activity. Another study showed TGF-β1-treated fibroblasts produce microvesicles with high miR-34a level which are able to induce tubular cell apoptosis in fibrotic kidney (Zhou et al, 2014). Furthermore, microRNA profiling also indicates that miR-34a is upregulated in bleomycin-induced pulmonary fibrosis suggesting it could be also play an important role in lung fibrosis (Honeyman et al, 2013; Xie et al, 2011).…”