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

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 fibro...

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Bibliographic Details
Published in:Journal of pharmacological sciences 2019-09, Vol.141 (1), p.70-78
Main Authors: Lyu, Huiyan, Li, Xin, Wu, Qi, Hao, Lirong
Format: Article
Language:English
Subjects:
Angiotensin II - adverse effects
Cells, Cultured
Fibrosis
Fused Kidney
Gene Expression
Humans
Kidney - pathology
Kidney Diseases - genetics
Kidney Diseases - pathology
Kidney Diseases - therapy
MicroRNAs - genetics
MicroRNAs - metabolism
Molecular Targeted Therapy
PPAR alpha - metabolism
Signal Transduction - physiology
Smad3 Protein - metabolism
Transforming Growth Factor beta1 - metabolism
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Summary: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.
ISSN:1347-8613
1347-8648
DOI:10.1016/j.jphs.2019.09.007