65 82

Cited 54 times in

Transforming growth factor β1 (TGF-β1) enhances expression of profibrotic genes through a novel signaling cascade and microRNAs in renal mesangial cells

 Nancy E. Castro  ;  Mitsuo Kato  ;  Jung Tak Park  ;  Rama Natarajan 
 Journal of Biological Chemistry, Vol.289(42) : 29001-29013, 2014 
Journal Title
 Journal of Biological Chemistry 
Issue Date
3' Untranslated Regions ; Animals ; CCAAT-Binding Factor/metabolism ; Cells, Cultured ; Collagen Type IV/metabolism ; Diabetic Nephropathies/metabolism* ; Disease Progression ; Fibrosis ; Gene Expression Regulation* ; Kidney/metabolism ; Mesangial Cells/metabolism* ; Mice ; Mice, Inbred C57BL ; MicroRNAs/metabolism* ; Protein-Serine-Threonine Kinases/metabolism* ; Receptors, Transforming Growth Factor beta/metabolism* ; Signal Transduction ; Transforming Growth Factor beta1/pharmacology*
Collagen ; Diabetes ; Kidney ; MicroRNA (miRNA) ; Signaling
Increased expression of transforming growth factor-β1 (TGF-β1) in glomerular mesangial cells (MC) augments extracellular matrix accumulation and hypertrophy during the progression of diabetic nephropathy (DN), a debilitating renal complication of diabetes. MicroRNAs (miRNAs) play key roles in the pathogenesis of DN by modulating the actions of TGF-β1 to enhance the expression of profibrotic genes like collagen. In this study, we found a significant decrease in the expression of miR-130b in mouse MC treated with TGF-β1. In parallel, there was a down-regulation in miR-130b host gene 2610318N02RIK (RIK), suggesting host gene-dependent expression of this miRNA. TGF-β receptor 1 (TGF-βR1) was identified as a target of miR-130b. Interestingly, the RIK promoter contains three NF-Y binding sites and was regulated by NF-YC. Furthermore, NF-YC expression was inhibited by TGF-β1, suggesting that a signaling cascade, involving TGF-β1-induced decreases in NF-YC, RIK, and miR-130b, may up-regulate TGF-βR1 to augment expression of TGF-β1 target fibrotic genes. miR-130b was down-regulated, whereas TGF-βR1, as well as the profibrotic genes collagen type IV α 1 (Col4a1), Col12a1, CTGF, and PAI-1 were up-regulated not only in mouse MC treated with TGF-β1 but also in the glomeruli of streptozotocin-injected diabetic mice, supporting in vivo relevance. Together, these results demonstrate a novel miRNA- and host gene-mediated amplifying cascade initiated by TGF-β1 that results in the up-regulation of profibrotic factors, such as TGF-βR1 and collagens associated with the progression of DN.
Files in This Item:
T201406375.pdf Download
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Park, Jung Tak(박정탁) ORCID logo https://orcid.org/0000-0002-2325-8982
RIS (EndNote)
XLS (Excel)
사서에게 알리기


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.