1. Academic Validation
  2. Overexpression of microRNA-21 mediates Ang II-induced renal fibrosis by activating the TGF-β1/Smad3 pathway via suppressing PPARα

Overexpression of microRNA-21 mediates Ang II-induced renal fibrosis by activating the TGF-β1/Smad3 pathway via suppressing PPARα

  • J Pharmacol Sci. 2019 Sep;141(1):70-78. doi: 10.1016/j.jphs.2019.09.007.
Huiyan Lyu 1 Xin Li 1 Qi Wu 1 Lirong Hao 2
Affiliations

Affiliations

  • 1 Department of Nephrology, First Affiliated Hospital of Harbin Medical University, Heilongjiang, 150001, People's Republic of China.
  • 2 Department of Nephrology, First Affiliated Hospital of Harbin Medical University, Heilongjiang, 150001, People's Republic of China. Electronic address: lironghaohmu@163.com.
Abstract

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; PPARα; Renal fibrosis; microRNA-21.

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