MicroRNA-302b mitigates renal fibrosis via inhibiting TGF-β/Smad pathway activation

Abstract

Renal fibrosis is one of the most significant pathological changes after ureteral obstruction. Transforming growth factor-β (TGF-β) signaling pathway plays essential roles in kidney fibrosis regulation. The aims of the present study were to investigate effects of microRNA-302b (miR-302b) on renal fibrosis, and interaction between miR-302b and TGF-β signaling pathway in murine unilateral ureteral obstruction (UUO) model. Microarray dataset GSE42716 was downloaded by retrieving Gene Expression Omnibus database. In accordance with bioinformatics analysis results, miR-302b was significantly down-regulated in UUO mouse kidney tissue and TGF-β1-treated HK-2 cells. Masson's trichrome staining showed that miR-302b mimics decreased renal fibrosis induced by UUO. The increased mRNA expression of collagen I and α-smooth muscle actin (α-SMA) and decreased expression of E-cadherin were reversed by miR-302b mimics. In addition, miR-302b up-regulation also inhibited TGF-β1-induced epithelial mesenchymal transition (EMT) of HK-2 cells by restoring E-cadherin expression and decreasing α-SMA expression. miR-302b mimics suppressed both luciferase activity and protein expression of TGF-βR2. However, miR-302b inhibitor increased TGF-βR2 luciferase activity and protein expression. Meanwhile, miR-302b mimics inhibited TGF-βR2 mRNA expression and decreased Smad2 and Smad3 phosphorylation in vivo and in vitro . Furthermore, over-expression of TGF-βR2 restored the miR-302b-induced decrease of collagen I and α-SMA expression. In conclusion, this study demonstrated that miR-302b attenuated renal fibrosis by targeting TGF-βR2 to suppress TGF-β/Smad signaling activation. Our findings showed that elevating renal miR-302b levels may be a novel therapeutic strategy for preventing renal fibrosis.

Hypoxia enhances anti-fibrotic properties of extracellular vesicles derived from hiPSCs via the miR302b-3p/TGFβ/SMAD2 axis

“…This effect was abolished when EV-H5 were used along with the miR302b-3p inhibitor. Our results are in line with and extended data from other reports showing the inhibitory effect of miR-302 family members on TGFβ/SMAD2 signaling [ 23 , 78 ]. Based on sequence similarity, these miRNAs may cooperate and target a similar set of genes, boosting the biological effect.…”

Estradiol Ameliorates Acute Kidney Ischemia-Reperfusion Injury by Inhibiting the TGF-βRI-SMAD Pathway

“…Conditional knockout of the TGF-βRII/Smad2 pathway reportedly exerts a protective effect on acute renal injury by alleviating cell necroptosis, apoptosis, and inflammation ( 41 ). Overexpression of TGF-βRII increases the expression of collagen I and α-SMA, which are closely related to renal fibrosis ( 42 ). However, the role of TGF-β1 in renal IRI is still unclear.…”

Recent advances in extracellular vesicle engineering and its applications to regenerative medicine

“…As a result, in an in vivo study, a reduction in fibrosis-associated markers expression levels, including α-SMA and E-cadherin, was observed. This suggests an anti-fibrosis effect in a mouse model of CKD that shows improvements in the levels of BUN and serum creatinine [ 83 , 84 ]. When Tanshinone IIA (TSA), an effective drug for myocardial ischemia-reperfusion injury (MI/RI), was treated with UCMSC and its EVs were isolated and delivered into the myocardium in vivo, it demonstrated an effect of reducing the size of the infarct while improving heart function, compared to non-treated group.…”