Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells
Abstract Epigenetic modulation may underlie the progression of diabetic nephropathy (DN). Involvement of TGFB1 in mesangial fibrosis of DN led us to hypothesize that Tgfb1 DNA demethylation contributes to progression of DN. In primary mesangial cells from diabetic (db/db) mouse kidneys, demethylatio...
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2018
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oai:doaj.org-article:25e25c0186854cdaaea68a964729952f2021-12-02T15:08:02ZAberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells10.1038/s41598-018-34612-32045-2322https://doaj.org/article/25e25c0186854cdaaea68a964729952f2018-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34612-3https://doaj.org/toc/2045-2322Abstract Epigenetic modulation may underlie the progression of diabetic nephropathy (DN). Involvement of TGFB1 in mesangial fibrosis of DN led us to hypothesize that Tgfb1 DNA demethylation contributes to progression of DN. In primary mesangial cells from diabetic (db/db) mouse kidneys, demethylation of Tgfb1 DNA and upregulation of Tgfb1 mRNA progressed simultaneously. USF1 binding site in Tgfb1 promoter region were demethylated, and binding of USF1 increased, with decreased binding of DNMT1 in db/db compared with control. Given downregulation of Tgfb1 expression by folic acid, antioxidant Tempol reversed DNA demethylation, with increased and decreased recruitment of DNMT1 and USF1 to the promoter, resulting in decreased Tgfb1 expression in db/db mice. Addition of H2O2 to mesangial cells induced DNA demethylation and upregulated Tgfb1 expression. Finally, Tempol attenuated mesangial fibrosis in db/db mice. We conclude that aberrant DNA methylation of Tgfb1 due to ROS overproduction play a key to mesangial fibrosis during DN progression.Shigeyoshi ObaNobuhiro AyuzawaMitsuhiro NishimotoWakako KawarazakiKohei UedaDaigoro HirohamaFumiko Kawakami-MoriTatsuo ShimosawaTakeshi MarumoToshiro FujitaNature PortfolioarticlePrimary Mesangial CellsTGFB1 PromoterMesangial FibrosisTGFβ1 mRNA ExpressionUSF Binding SiteMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-16 (2018) |
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Primary Mesangial Cells TGFB1 Promoter Mesangial Fibrosis TGFβ1 mRNA Expression USF Binding Site Medicine R Science Q |
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Primary Mesangial Cells TGFB1 Promoter Mesangial Fibrosis TGFβ1 mRNA Expression USF Binding Site Medicine R Science Q Shigeyoshi Oba Nobuhiro Ayuzawa Mitsuhiro Nishimoto Wakako Kawarazaki Kohei Ueda Daigoro Hirohama Fumiko Kawakami-Mori Tatsuo Shimosawa Takeshi Marumo Toshiro Fujita Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells |
| description |
Abstract Epigenetic modulation may underlie the progression of diabetic nephropathy (DN). Involvement of TGFB1 in mesangial fibrosis of DN led us to hypothesize that Tgfb1 DNA demethylation contributes to progression of DN. In primary mesangial cells from diabetic (db/db) mouse kidneys, demethylation of Tgfb1 DNA and upregulation of Tgfb1 mRNA progressed simultaneously. USF1 binding site in Tgfb1 promoter region were demethylated, and binding of USF1 increased, with decreased binding of DNMT1 in db/db compared with control. Given downregulation of Tgfb1 expression by folic acid, antioxidant Tempol reversed DNA demethylation, with increased and decreased recruitment of DNMT1 and USF1 to the promoter, resulting in decreased Tgfb1 expression in db/db mice. Addition of H2O2 to mesangial cells induced DNA demethylation and upregulated Tgfb1 expression. Finally, Tempol attenuated mesangial fibrosis in db/db mice. We conclude that aberrant DNA methylation of Tgfb1 due to ROS overproduction play a key to mesangial fibrosis during DN progression. |
| format |
article |
| author |
Shigeyoshi Oba Nobuhiro Ayuzawa Mitsuhiro Nishimoto Wakako Kawarazaki Kohei Ueda Daigoro Hirohama Fumiko Kawakami-Mori Tatsuo Shimosawa Takeshi Marumo Toshiro Fujita |
| author_facet |
Shigeyoshi Oba Nobuhiro Ayuzawa Mitsuhiro Nishimoto Wakako Kawarazaki Kohei Ueda Daigoro Hirohama Fumiko Kawakami-Mori Tatsuo Shimosawa Takeshi Marumo Toshiro Fujita |
| author_sort |
Shigeyoshi Oba |
| title |
Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells |
| title_short |
Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells |
| title_full |
Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells |
| title_fullStr |
Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells |
| title_full_unstemmed |
Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells |
| title_sort |
aberrant dna methylation of tgfb1 in diabetic kidney mesangial cells |
| publisher |
Nature Portfolio |
| publishDate |
2018 |
| url |
https://doaj.org/article/25e25c0186854cdaaea68a964729952f |
| work_keys_str_mv |
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| _version_ |
1718388239599927296 |