Epigenetic Histone Modifications Involved in Profibrotic Gene Regulation by 12/15-Lipoxygenase and Its Oxidized Lipid Products in Diabetic Nephropathy.
OBJECTIVE
Epigenetic mechanisms, including histone post-translational modifications and DNA methylation, are implicated in the pathogenesis of diabetic nephropathy (DN), but the mediators are not well known. Moreover, although dyslipidemia contributes to DN, epigenetic changes triggered by lipids are unclear. In diabetes, increased expression of 12/15-lipoxygenase (12/15-LO) enhances oxidized lipids such as 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which promote oxidant stress, glomerular and mesangial cell (MC) dysfunction, and fibrosis, and mediate the actions of profibrotic growth factors. We hypothesized that 12/15-LO and its oxidized lipid products can regulate epigenetic mechanisms mediating profibrotic gene expression related to DN.


RESULTS
12(S)-HETE increased profibrotic gene expression and enrichment of permissive histone lysine modifications at their promoters in MCs. 12(S)-HETE also increased protein levels of SET7, a histone H3 lysine 4 methyltransferase, and promoted its nuclear translocation and enrichment at profibrotic gene promoters. Furthermore, SET7 (Setd7) gene silencing inhibited 12(S)-HETE-induced profibrotic gene expression. 12/15-LO (Alox15) gene silencing or genetic knockout inhibited transforming growth factor-β1 (TGF-β1)-induced expression of Setd7 and profibrotic genes and histone modifications in MCs. Furthermore, 12/15-LO knockout in mice ameliorated key features of DN and abrogated increases in renal SET7 and profibrotic genes. Additionally, 12/15-LO siRNAs in vivo blocked increases in renal SET7 and profibrotic genes in diabetic mice.


CONCLUSIONS
These novel results demonstrate for the first time that 12/15-LO-derived oxidized lipids regulate histone modifications associated with profibrotic gene expression in MCs, and 12/15-LO can mediate similar actions of TGF-β1 and diabetes. Targeting 12/15-LO might be a useful strategy to inhibit key epigenetic mechanisms involved in DN.
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.|2 Department of Nephrology, First Hospital of Jilin University , Changchun, China .
Hang
H
Yuan
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.
Marpadga A
MA
Reddy
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.
Supriya
S
Deshpande
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.|3 Department of Nephrology, Second Hospital of Jilin University , Changchun, China .
Ye
Y
Jia
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.|4 Department of Internal Medicine, College of Medicine, Yonsei University , Seoul, Republic of Korea.
Jung Tak
JT
Park
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.
Linda L
LL
Lanting
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.
Wen
W
Jin
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.
Mitsuo
M
Kato
2 Department of Nephrology, First Hospital of Jilin University , Changchun, China .
Zhong Gao
ZG
Xu
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.
Sadhan
S
Das
1 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope , Duarte, California.
Rama
R
Natarajan
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D059014:High-Throughput Nucleotide Sequencing; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D050356:Lipid Metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic; D051381:Rats; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
C475064:12-15-lipoxygenase; D006657:Histones; D006893:Hydroxyeicosatetraenoic Acids; D016212:Transforming Growth Factor beta; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D011495:Histone-Lysine N-Methyltransferase