The regulatory role of a novel miRNA, miR-378, was determined in the development of fibrosis through repression of the MAPK1 pathway, miR-378 and fibrotic gene expression was examined in streptozotocin (STZ)-induced diabetic mice at 18 weeks or in unilateral ureteral obstruction (UUO) mice at 7 days. miR-378 transfection of proximal tubular epithelial cells, NRK52E and mesangial cells was assessed with/without endogenous miR-378 knockdown using the locked nucleic acid (LNA) inhibitor. NRK52E cells were co-transfected with the mothers against decapentaplegic homolog 3 (SMAD3) CAGA reporter and miR-378 in the presence of transforming growth factor-β (TGF-β1) was assessed. Quantitative polymerase chain reaction (qPCR) showed a significant reduction in miR-378 (P<0.05) corresponding with up-regulated type I collagen, type IV collagen and α-smooth muscle actin (SMA) in kidneys of STZ or UUO mice, compared with controls. TGF-β1 significantly increased mRNA expression of type I collagen (P<0.05), type IV collagen (P<0.05) and α-SMA (P<0.05) in NRK52E cells, which was significantly reduced (P<0.05) following miR-378 transfection and reversed following addition of the LNA inhibitor of endogenous miR-378. Overexpression of miR-378 inhibited mesangial cell expansion and proliferation in response to TGF-β1, with LNA–miR-378 transfection reversing this protective effect, associated with cell morphological alterations. The protective function of MAPK1 on miR-378 was shown in kidney cells treated with the MAPK1 inhibitor, selumetinib, which inhibited mesangial cell hypertrophy in response to TGF-β1. Taken together, these results suggest that miR-378 acts via regulation of the MAPK1 pathway. These studies demonstrate the protective function of MAPK1, regulated by miR-378, in the induction of kidney cell fibrosis and mesangial hypertrophy.
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March 2017
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Cover Image
Phase contrast microscopy showing primary human mesangial cells in culture. Quantification of cell area showed that exposure of mesangial cells to the pro-fibrotic growth factor (TGF-β1) induced morphological cell expansion and hypertrophy, which was reversed following the overexpression of miR-378. Interestingly, transfection of a miR-378 inhibitor induced the expansion of mesangial cells, highlighting the regulatory role of miR-378 in mesangial hypertrophy. Please see the article by Wang et al. (pages 411-423).
Research Article|
February 17 2017
miR-378 reduces mesangial hypertrophy and kidney tubular fibrosis via MAPK signalling
Bo Wang;
Bo Wang
1Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton
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Kevin Yao;
Kevin Yao
1Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton
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Andrea F. Wise;
Andrea F. Wise
1Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton
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Ricky Lau;
Ricky Lau
1Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton
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Hsin-Hui Shen;
Hsin-Hui Shen
2Department of Materials Engineering, Monash University, Clayton
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Greg H. Tesch;
Greg H. Tesch
3Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia
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Sharon D. Ricardo
1Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton
Correspondence: Professor Sharon D. Ricardo (email [email protected])
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Publisher: Portland Press Ltd
Received:
July 27 2016
Revision Received:
December 10 2016
Accepted:
January 03 2017
Accepted Manuscript online:
January 04 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (5): 411–423.
Article history
Received:
July 27 2016
Revision Received:
December 10 2016
Accepted:
January 03 2017
Accepted Manuscript online:
January 04 2017
Citation
Bo Wang, Kevin Yao, Andrea F. Wise, Ricky Lau, Hsin-Hui Shen, Greg H. Tesch, Sharon D. Ricardo; miR-378 reduces mesangial hypertrophy and kidney tubular fibrosis via MAPK signalling. Clin Sci (Lond) 1 March 2017; 131 (5): 411–423. doi: https://doi.org/10.1042/CS20160571
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