Cargando…
Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells
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 Tgfb...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218490/ https://www.ncbi.nlm.nih.gov/pubmed/30397232 http://dx.doi.org/10.1038/s41598-018-34612-3 |
_version_ | 1783368461830848512 |
---|---|
author | Oba, Shigeyoshi Ayuzawa, Nobuhiro Nishimoto, Mitsuhiro Kawarazaki, Wakako Ueda, Kohei Hirohama, Daigoro Kawakami-Mori, Fumiko Shimosawa, Tatsuo Marumo, Takeshi Fujita, Toshiro |
author_facet | Oba, Shigeyoshi Ayuzawa, Nobuhiro Nishimoto, Mitsuhiro Kawarazaki, Wakako Ueda, Kohei Hirohama, Daigoro Kawakami-Mori, Fumiko Shimosawa, Tatsuo Marumo, Takeshi Fujita, Toshiro |
author_sort | Oba, Shigeyoshi |
collection | PubMed |
description | 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 H(2)O(2) 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 | Online Article Text |
id | pubmed-6218490 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62184902018-11-07 Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells Oba, Shigeyoshi Ayuzawa, Nobuhiro Nishimoto, Mitsuhiro Kawarazaki, Wakako Ueda, Kohei Hirohama, Daigoro Kawakami-Mori, Fumiko Shimosawa, Tatsuo Marumo, Takeshi Fujita, Toshiro Sci Rep Article 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 H(2)O(2) 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. Nature Publishing Group UK 2018-11-05 /pmc/articles/PMC6218490/ /pubmed/30397232 http://dx.doi.org/10.1038/s41598-018-34612-3 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Oba, Shigeyoshi Ayuzawa, Nobuhiro Nishimoto, Mitsuhiro Kawarazaki, Wakako Ueda, Kohei Hirohama, Daigoro Kawakami-Mori, Fumiko Shimosawa, Tatsuo Marumo, Takeshi Fujita, Toshiro Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells |
title | 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_short | Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells |
title_sort | aberrant dna methylation of tgfb1 in diabetic kidney mesangial cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218490/ https://www.ncbi.nlm.nih.gov/pubmed/30397232 http://dx.doi.org/10.1038/s41598-018-34612-3 |
work_keys_str_mv | AT obashigeyoshi aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT ayuzawanobuhiro aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT nishimotomitsuhiro aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT kawarazakiwakako aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT uedakohei aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT hirohamadaigoro aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT kawakamimorifumiko aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT shimosawatatsuo aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT marumotakeshi aberrantdnamethylationoftgfb1indiabetickidneymesangialcells AT fujitatoshiro aberrantdnamethylationoftgfb1indiabetickidneymesangialcells |