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Drug Des Devel Ther. 2018 Aug 6;12:2431-2442. doi: 10.2147/DDDT.S170840. eCollection 2018.

Astragaloside IV improves renal function and fibrosis via inhibition of miR-21-induced podocyte dedifferentiation and mesangial cell activation in diabetic mice.

Wang X1,2, Gao Y1,2, Tian N1, Zou D2, Shi Y1, Zhang N1,2.

Author information

1
Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China, dfyynfm@163.com.
2
Department of Endocrinology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing, China, dfyynfm@163.com.

Abstract

Background:

Podocyte dedifferentiation and mesangial cell (MC) activation play an important role in many glomerular diseases associated with fibrosis. MicroRNA-21 (miR-21) is closely linked to renal fibrosis, but it is unknown whether and how miR-21 promotes podocyte dedifferentiation and MC activation and whether astragaloside IV (AS-IV) improves renal function and fibrosis through the regulation of miR-21.

Materials and methods:

Cultured MCs, primary mouse podocytes, and diabetic KK-Ay mice were treated with AS-IV. Cell transfection, Western blot, real-time PCR, immunofluorescence assay, immunohistochemical assay, and electronic microscopy were used to detect the markers of podocyte dedifferentiation and MC activation and to observe the renal morphology.

Results:

Our data showed that miR-21 expression was increased and that AS-IV decreased miR-21 levels in cells, serum, and kidney. Overexpressed miR-21 promoted podocyte dedifferentiation and MC activation, and treatment with AS-IV reversed this effect. Furthermore, the overexpression of miR-21 activated the β-catenin pathway and the transforming growth factor (TGF)-β1/Smads pathway in the process of podocyte dedifferentiation and MC activation, which was abolished by AS-IV treatment. In addition, both the Wnt/β-catenin pathway inhibitor XAV-939 and the TGF-β1/Smads pathway inhibitor SB431542 reversed the effect of AS-IV. Furthermore, AS-IV improved renal function and fibrosis in diabetic KK-Ay mice.

Conclusion:

Our results indicated that AS-IV ameliorates renal function and renal fibrosis by inhibiting miR-21 overexpression-induced podocyte dedifferentiation and MC activation in diabetic kidney disease. These findings pave way for future studies investigating AS-IV as a potential therapeutic agent in the management of glomerular diseases.

KEYWORDS:

TGF-β1/Smads pathway; astragaloside IV; mesangial cell activation; miR-21; podocyte dedifferentiation; renal fibrosis; β-catenin pathway

PMID:
30122901
PMCID:
PMC6084069
DOI:
10.2147/DDDT.S170840
[Indexed for MEDLINE]
Free PMC Article

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