MicroRNA-34a Promotes Renal Fibrosis by Downregulation of Klotho in Tubular Epithelial Cells

Abstract

Renal fibrosis is the main pathological characteristic of chronic kidney disease (CKD), whereas the underlying mechanisms of renal fibrosis are not clear yet. Herein, we found an increased expression of microRNA-34a (miR-34a) in renal tubular epithelial cells of patients with renal fibrosis and mice undergoing unilateral ureteral obstruction (UUO). In miR-34a À/À mice, miR-34a deficiency attenuated the progression of renal fibrosis following UUO surgery. The miR-34a overexpression promoted epithelial-to-mesenchymal transition (EMT) in cultured human renal tubular epithelial HK-2 cells, which was accompanied by sharp downregulation of Klotho, an endogenous inhibitor of renal fibrosis. Luciferase reporter assay revealed that miR-34a downregulated Klotho expression though direct binding with the 3 0 UTR of Klotho. Conversely, overexpression of Klotho prevented miR-34a-induced EMT in HK-2 cells. Furthermore, results showed that miR-34a was induced by transforming growth factor b1 (TGF-b1) through p53 activation, whereas dihydromyricetin could inhibit TGF-b1-induced miR-34a overexpression. Accordingly, dihydromyricetin administration dramatically restored the aberrant upregulation of miR-34a and Klotho reduction in obstructed kidney, and markedly ameliorated renal fibrosis in the Adriamycin nephropathy and UUO model mice. These findings suggested that miR-34a plays an important role in the progression of renal fibrosis, which provides new insights into the pathogenesis and treatment of CKD.

Dihydromyricetin inhibits cell proliferation, migration, invasion and promotes apoptosis via regulating miR-21 in Human Cholangiocarcinoma Cells

“…So far, there has been no study to report that dihydromyricetin exerts the anti-tumor effect by modulating miRNA. However, recent studies by Yang et al found that dihydromyricietin administration significantly restored the abnormal upregulation of miR-34a and ameliorated renal fibrosis in model mice [27]. Moreover, our previous study has shown that dihydromyricetin attenuates TNF-alpha-induced endothelial dysfunction through regulating miR-21 in HUVEC cells [10].…”

Negative Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

“…During the past few years, many studies have shown that the expression levels of miRNAs and their downstream target genes are closely associated with the progression of RF [3,4,2,10]. After applying various bioinformatics technologies as shown above, we found that Ptch1 is the most promising target mRNA of miR-342-5p in RF.…”

“…MicroRNAs (miRNAs) are endogenous small non-coding 21-25 nucleotide singlestranded RNAs s. miRNAs regulate gene expression by promoting the degradation of mRNAs or inhibiting the translation of mRNAs. miRNAs are involved in the development of various diseases, and several miRNAs are closely associated with RF, including miR-184, miR-34a, and miR-199a-3p [2][3][4]. Our review showed the recent progress, biological functions, and clinical applications of miRNAs in the progression of RF [5].…”

Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

“…In addition, both miR132-3p and miR214 have been found to be upregulated in various models of kidney diseases and associated with inflammation, apoptosis, myofibroblast activation, and dysregulation of the extracellular matrix (Denby et al, 2011(Denby et al, , 2014Bijkerk et al, 2016). Furthermore, attenuation of these miRNAs through inhibition or silencing has been shown to ameliorate the various forms of kidney diseases by downregulating pathways and processes favoring the progression of injury and fibrosis (Denby et al, 2011;Liu et al, 2019). Bioinformatic meta-analysis was performed on the predicted and validated target genes of these 7 miRNAs for the relative pathways to be identified.…”