Please use this identifier to cite or link to this item:
https://repository.monashhealth.org/monashhealthjspui/handle/1/39470
Title: | miR-378 reduces mesangial hypertrophy and kidney tubular fibrosis via MAPK signalling. | Authors: | Ricardo S.D.;Wang B.;Yao K.;Wise A.F.;Lau R.;Shen H.-H.;Tesch G.H. | Monash Health Department(s): | Nephrology | Institution: | (Wang, Yao, Wise, Lau, Ricardo) Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia (Shen) Department of Materials Engineering, Monash University, Clayton, Australia (Tesch) Department of Nephrology, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia | Issue Date: | 23-Mar-2017 | Copyright year: | 2017 | Publisher: | Portland Press Ltd | Place of publication: | United Kingdom | Publication information: | Clinical Science. 131 (5) (pp 411-423), 2017. Date of Publication: 2017. | Journal: | Clinical Science | 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-beta (TGF-beta1) 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-beta1 significantly increased mRNA expression of type I collagen (P < 0.05), type IV collagen (P < 0.05) and alpha-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-beta1, 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-beta1. 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.Copyright © 2017 The Author(s). | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1042/CS20160571 | Link to associated publication: | Click here for full text options | PubMed URL: | 28053239 [http://www.ncbi.nlm.nih.gov/pubmed/?term=28053239] | ISSN: | 0143-5221 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/39470 | Type: | Article | Subjects: | article cell expansion cell proliferation cell protection cell structure controlled study drug efficacy drug mechanism gene expression regulation gene repression gene silencing genetic transfection human human cell *kidney hypertrophy/pc [Prevention] kidney proximal tubule kidney tubule cell *kidney tubule damage/pc [Prevention] luciferase assay male mesangium cell mouse nonhuman *obstruction-induced renal fibrosis/pc [Prevention] polymerase chain reaction priority journal quantitative analysis animal tissue renal protection reporter gene signal transduction streptozotocin-induced diabetes mellitus upregulation alpha smooth muscle actin/ec [Endogenous Compound] *antifibrotic agent/dv [Drug Development] *antifibrotic agent/pd [Pharmacology] beta actin/ec [Endogenous Compound] collagen type 1/ec [Endogenous Compound] collagen type 4/ec [Endogenous Compound] fibronectin/ec [Endogenous Compound] locked nucleic acid messenger RNA/ec [Endogenous Compound] *microRNA/dv [Drug Development] *microRNA/ec [Endogenous Compound] *microRNA/pd [Pharmacology] *mitogen activated protein kinase 1/ec [Endogenous Compound] recombinant transforming growth factor beta1 selumetinib/dv [Drug Development] selumetinib/pd [Pharmacology] Smad3 protein/ec [Endogenous Compound] streptozocin transforming growth factor beta1/ec [Endogenous Compound] unclassified drug *urinary tract agent/dv [Drug Development] *urinary tract agent/pd [Pharmacology] *microRNA 378/dv [Drug Development] *microRNA 378/ec [Endogenous Compound] *microRNA 378/pd [Pharmacology] rat animal model animal experiment animal cell gene repression gene silencing genetic transfection human human cell *kidney hypertrophy / *prevention kidney proximal tubule kidney tubule cell *kidney tubule damage / *prevention luciferase assay male mesangium cell mouse nonhuman *obstruction-induced renal fibrosis / *prevention polymerase chain reaction priority journal quantitative analysis rat renal protection reporter gene signal transduction Article upregulation streptozotocin-induced diabetes mellitus cell expansion cell proliferation cell protection cell structure controlled study drug efficacy drug mechanism gene expression regulation animal cell animal experiment animal model animal tissue |
Appears in Collections: | Articles |
Show full item record
Items in Monash Health Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.