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Angiotensin II (Ang II) is an important profibrotic factor, and the tumor-promoting microRNA miR-21 was recently linked to fibrotic disorders. We aimed to investigate whether and how miR-21 mediates Ang II-induced renal fibrosis. In renal tubular epithelial cells, Ang II upregulated miR-21 and fibrosis-related indicators but decreased PPARα expression. miR-21 overexpression promoted PPARα downregulation, activated the TGF-β1/Smad3 pathway and induced fibrogenesis, while miR-21 suppression exerted opposite effects. In Ang II-treated cells, reduced PPARα expression, TGF-β1/Smad3 pathway activation and fibrogenesis were all exacerbated by miR-21 upregulation but alleviated by miR-21 inhibition. The dual-luciferase assay confirmed PPARα as the target of miR-21. PPARα silencing alone could overactivate the TGF-β1/Smad3 pathway in the presence or absence of Ang II. Importantly, the regulatory effects of miR-21 knockdown and the angiotensin type 1 receptor blocker losartan alone or in combination on the PPARα/TGF-β1/Smad3 pathway in Ang II-treated cells were almost the same. More crucially, PPARα restoration abolished the profibrotic effect of miR-21 overexpression. In addition, inhibiting miR-21 in Ang II-treated mice effectively ameliorated the abnormally activated PPARα/TGF-β1/Smad3 pathway, albuminuria, and renal fibrosis without lowering blood pressure. These results demonstrated that miR-21 extensively mediates Ang II-induced kidney fibrosis via amplifying the TGF-β1/Smad3 pathway by targeting PPARα. Keywords: Angiotensin II, microRNA-21, PPARα, Renal fibrosis

TGF-β1-induced excessive deposition of ECM and EMT process of tubular epithelial cells play critical roles in the development and progression of fibrosis in diabetic nephropathy (DN). Orai1 has been demonstrated to be involved in TGF-β1-induced EMT via TGF-β/Smad3 pathway. We are aimed to explore the effects of miR-93 on TGF-β1-induced EMT process in HK2 cells. In this study, our data showed that miR-93 was dramatically decreased in renal tissues of patients with DN and TGF-β1-stimulated HK2 cells. Moreover, the decreased level of miR-93 was closely associated with the increased expression of Orai1. Overexpression of miR-93 decreased Orai1 expression, and then suppressed TGF-β1-mediated EMT and fibrogenesis. Next, we predicted that the Orai1 was a potential target gene of miR-93, and demonstrated that miR-93 could directly target Orai1. SiRNA targeting Orai1 was sufficient to suppress TGF-β1-induced EMT and fibrogenesis in HK2 cells. Furthermore, Overexpression of Orai1 partially reversed the protective effect of miR-93 overexpression on TGF-β1-mediated EMT and fibrogenesis in HK2 cells. Taken together, Orai1 and miR-93 significantly impact on the progression of TGF-β1-mediated EMT and fibrogenesis in HK2 cells, and they may represent novel targets for the prevention strategies of fibrosis in the context of DN. Keywords: Diabetic nephropathy, MicroRNA-93, Epithelial-mesenchymal transition, Renal fibrogenesis, Orai1