miR-378 reduces mesangial hypertrophy and kidney tubular fibrosis via MAPK signalling

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13 Citations (Scopus)

Abstract

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 a-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.

Original languageEnglish
Pages (from-to)411-423
Number of pages13
JournalClinical Science
Volume131
Issue number5
DOIs
Publication statusPublished - 2017

Keywords

  • miRNA
  • kidney fibrosis
  • diabetic nephropathy
  • mesangial cells
  • TGF-β1

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