title: Involvement of Histone Lysine Methylation in p21 Gene Expression in Rat Kidney In Vivo and Rat Mesangial Cells In Vitro under Diabetic Conditions.
abstract: Diabetic nephropathy (DN), a common complication associated with type 1 and type 2 diabetes mellitus (DM), characterized by glomerular mesangial expansion, inflammation, accumulation of extracellular matrix (ECM) protein, and hypertrophy, is the major cause of end-stage renal disease (ESRD). Increasing evidence suggested that p21-dependent glomerular and mesangial cell (MC) hypertrophy play key roles in the pathogenesis of DN. Recently, posttranscriptional modifications (PTMs) have uncovered novel molecular mechanisms involved in DN. However, precise regulatory mechanism of histone lysine methylation (HKme) mediating p21 related hypertrophy associated with DN is not clear. We evaluated the roles of HKme and histone methyltransferase (HMT) SET7/9 in p21 gene expression in glomeruli of diabetic rats and in high glucose- (HG-) treated rat mesangial cells (RMCs). p21 gene expression was upregulated in diabetic rats glomeruli; chromatin immunoprecipitation (ChIP) assays showed decreased histone H3-lysine9-dimethylation (H3K9me2) accompanied with enhanced histone H3-lysine4-methylation (H3K4me1/3) and SET7/9 occupancies at the p21 promoter. HG-treated RMCs exhibited increased p21 mRNA, H3K4me level, SET7/9 recruitment, and inverse H3K9me, which were reversed by TGF-β1 antibody. These data uncovered key roles of H3Kme and SET7/9 responsible for p21 gene expression in vivo and in vitro under diabetic conditions and confirmed preventive effect of TGF-β1 antibody on DN.
authors.affiliation: Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Xiangjun
authors.identifier: 0000-0002-8986-7203
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Nephrology, 2nd Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Chaoyuan
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Nephrology, 2nd Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Nephrology, 2nd Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Peihe
authors.initials: P
authors.lastname: Cui
authors.affiliation: Department of Nephrology, 2nd Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Nephrology, 2nd Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Qiaoyan
authors.identifier: 0000-0003-3725-8067
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Endocrinology, 208th Hospital of Chinese PLA, Changchun, Jilin 130062, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Nephrology, 2nd Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Nephrology, 2nd Hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Guangdong
authors.identifier: 0000-0002-2899-7899
authors.initials: G
authors.lastname: Sun
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D042421:Histone Code; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000378:metabolism*; D008239:Lysine; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D008745:Methylation; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors
chemical_list: D000906:Antibodies; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D011495:Histone-Lysine N-Methyltransferase; D005947:Glucose; D008239:Lysine