microRNA-199a downregulation alleviates hyperuricemic nephropathy via the PPARγ/β-catenin axis

Abstract

Hyperuricemia always develops into hyperuricemic nephropathy (HN). The role of microRNA (miR) in HN is less studied. We aimed to discuss the role of miR-199a in HN. The expression of miR-199a and PPARc in renal tissues of HN rats was detected. The targeting relation between miR-199a and PPARc was verified. The contents of SCr, UA, BUN, and mALB, renal injury-relevant biomarkers were detected, and the pathological changes of renal tissue and renal interstitial fibrosis were observed by histological staining. After miR-199a and PPARc knockdown, the contents of SCr, BUN, and mALB and renal interstitial fibrosis were estimated. Collectively, overexpression of miR-199a aggravated the renal injury in HN rats. By contrast, inhibition of miR-199a weakened renal injury, as evidenced by decreased contents of SCr, UA, BUN, and mALB, and mitigated renal interstitial fibrosis. miR-199a targeted PPARc. Silencing of PPARc upregulated the levels of downstream genes of b-catenin and the contents of SCr, UA, BUN, and mALB and deteriorated renal interstitial fibrosis. Moreover, the silencing of PPARc blocked the alleviative effects of miR-199a inhibitor on the renal injury. Overall, miR-199a targets PPARc and activates the b-catenin pathway, thus aggravating HN, which might provide a future target for the treatment of HN.

Pioglitazone Protects Tubular Epithelial Cells during Kidney Fibrosis by Attenuating miRNA Dysregulation and Autophagy Dysfunction Induced by TGF-β

“…The miR-199a-5p and -3p can be generated from miR-199a-1 and -2 precursors and both can influence the TGF-β pathway. For instance, miR-199a-5p was reported to inhibit endoplasmic reticulum stress in renal ischemia-reperfusion (I/R) injury [45] and to downregulate PPARγ, exacerbating renal interstitial fibrosis in rats with hyperuricemia [28]. Elevated miR-199a-5p has been reported in mouse and human CKD as well, underscoring its potential importance [30].…”

“…Both miR-199a-3p and miR199a-5p are potential regulatory factors of TGF-β-mediated pathological renal processes [28][29][30]. TGF-β administration markedly increased the expressions of both miR-199a-3p and miR-199a-5p in primary mouse tubular epithelial cells, which were inhibited by pioglitazone (Figure 5C,E).…”

“…Numerous miRNAs have been identified in acute or chronic kidney diseases, such as miR-21-5p, which strongly correlates with fibrosis progression [26]. TGF-β also induces pro-fibrotic miR-130 in human renal proximal tubular epithelial cells [27] and miR-199a in the kidneys of hypertensive rats as well [28]. The miR-199a forms a pre-miR that undergoes RNA processing to yield miR-199a-5p and miR-199a-3p.…”

Characterizations of microRNAs involved in the molecular mechanisms underlying the therapeutic effects of noni (Morinda citrifolia L.) fruit juice on hyperuricemia in mice

“…For example, the increasing evidence has suggested that the development of hyperuricemia and gout is regulated at the post transcriptional level with strong involvement of miRNAs ( 24 ). Furthermore, studies have revealed abnormal expressions of miRNAs involved in hyperuricemia and the association between serum UA concentration and altered expressions of miRNAs ( 25 ). In particular, miRNAs could regulate the expression of urate transporter genes, e.g., miR-34a regulates the mRNA of the solute carrier family 22 member 12 ( SLC22A12 ) gene to ultimately repress the uric acid transporter 1 (URAT1) expression in the animal model of hyperuricemia ( 26 ).…”