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Abstract
Renal fibrosis denotes a common complication of diabetic nephropathy and is a predominant cause of end-stage renal disease. Despite the association between microRNAs (miRNAs or miRs) and renal fibrosis, miRNAs have been reported to play a vital role in the development of chronic renal fibrosis. Therefore, the aim of the present study was to investigate the possible function of miR-101a in chronic renal fibrosis. Initially, microarray-based gene expression profiling of renal fibrosis was employed to screen the differentially expressed genes. An in vivo mouse model of chronic renal fibrosis induced by a unilateral ureteral obstruction (UUO) and an in vitro cell model induced by aristolochic acid (AA) were constructed. miR-101a expression was examined using a fluorescence in situ hybridization (FISH) assay and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Then, the interaction between miR-101a and KDM3A was identified using an online website combined with a dual-luciferase reporter assay. Finally, gain- and loss-of-function experiments were conducted to elucidate the effect of miR-101a on the expression of Col1a1, fibronectin, α-smooth muscle actin (α-SMA), and YAP-TGF-β (transforming growth factor β)-Smad signaling pathway-related genes, as well as the degree of renal fibrosis. miR-101a was poorly expressed while KDM3A was robustly induced in chronic renal fibrosis tissues and cells. In addition, miR-101a could target and downregulate KDM3A expression, which led to elevated TGIF1, inhibited expression of Collagen I (Col1a1), fibronectin, α-SMA, YAP1, and TGF-β2 along with the extent of Smad2/3 phosphorylation, as well as delayed renal fibrosis degree. Besides, overexpressed YAP/TGF-β2 or inhibited TGIF1 partially restored the inhibitory effect of miR-101a on chronic renal fibrosis. Taken together, miR-101a could potentially slow down chronic renal fibrosis by the inactivation of the YAP-TGF-β-Smad signaling pathway via KDM3A, highlighting the potential of miR-101a as a therapeutic target for chronic renal fibrosis treatment.
Highlights
Renal fibrosis, featured by glomerulosclerosis and tubulointerstitial fibrosis, is the final manifestation of chronic kidney diseases (CKDs).[1]
The Gene Expression Omnibus (GEO) database revealed that TGFB-induced factor homeobox 1 (TGIF1) of the TGF-b/Smad signaling pathway was found to be differentially expressed in the GEO: GSE66494 dataset, where it was highly expressed in renal fibrosis (Figure 1A)
Emerging evidence has highlighted the function of miRNAs in renal fibrosis, which facilitates the process of early diagnosis and treatment of renal diseases.[19]
Summary
Renal fibrosis, featured by glomerulosclerosis and tubulointerstitial fibrosis, is the final manifestation of chronic kidney diseases (CKDs).[1] Renal fibrosis and CKD have been shown to affect 10% of the world’s population, where adults above age 70 account for 50% of the affected individuals.[2] Factors that contribute to renal fibrosis include tubular epithelial-to-mesenchymal transition (EMT), activation of mesangial and fibroblast cells, inflammatory (monocyte, macrophage, and T cell) infiltration, and apoptosis.[3] In the event of chronic renal fibrosis, the activated interstitial fibroblasts are considered to be the main pathogenic mediators of renal disease.[4] At present, chronic renal fibrosis is incurable and the incidence of the affected patients has been increasing steadily all around the world.[5] it is important to elucidate the epigenetic mechanisms of chronic renal fibrosis in order to identify novel therapeutic approaches for CKD
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