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Deprecated: Implicit conversion from float 217.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Cell+Physiol 2015 ; 309 (9): C616-26 Nephropedia Template TP
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TGF-?1 epigenetically modifies Thy-1 expression in primary lung fibroblasts #MMPMID26333597
Neveu WA; Mills ST; Staitieh BS; Sueblinvong V
Am J Physiol Cell Physiol 2015[Nov]; 309 (9): C616-26 PMID26333597show ga
Idiopathic pulmonary fibrosis is a progressive lung disease that increases in incidence with age. We identified a profibrotic lung phenotype in aging mice characterized by an increase in the number of fibroblasts lacking the expression of thymocyte differentiation antigen 1 (Thy-1) and an increase in transforming growth factor (TGF)-?1 expression. It has been shown that Thy-1 expression can be epigenetically modified. Lung fibroblasts (PLFs) were treated with TGF-?1 ± DNA methyltransferase (DNMT) inhibitor 5-aza-2?-deoxycytidine (5-AZA) and analyzed for Thy-1 gene and protein expression, DNMT protein expression, and activity. ?-Smooth muscle actin (?-SMA) and collagen type 1 (Col1A1) gene and protein expression was assessed. PLFs were transfected with DNMT1 silencing RNA ± TGF-?1. TGF-?1 inhibited Thy-1 gene and protein expression in PLFs, and cotreatment with 5-AZA ameliorated this effect and appeared to inhibit DNMT1 activation. TGF-?1 induced Thy-1 promoter methylation as assessed by quantitative methyl PCR. Treatment with 5-AZA attenuated TGF-?1-induced Col1A1 gene and protein expression and ?-SMA gene expression (but not ?-SMA protein expression). Inhibiting DNMT1 with silencing RNA attenuated TGF-?1-induced DNMT activity and its downstream suppression of Thy-1 mRNA and protein expression as well as inhibited ?-SMA mRNA and Col1A1 mRNA and protein expression, and showed a decreased trend in Thy-1 promoter methylation. Immunofluorescence for ?-SMA suggested that 5-AZA inhibited stress fiber formation. These findings suggest that TGF-?1 epigenetically regulates lung fibroblast phenotype through methylation of the Thy-1 promoter. Targeted inhibition of DNMT in the right clinical context might prevent fibroblast to myofibroblast transdifferentiation and collagen deposition, which in turn could prevent fibrogenesis in the lung and other organs.