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-ß1 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-ß1 antibody on DN.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/genetics , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Type 1/genetics , Diabetic Nephropathies/genetics , Histone Code , Histone-Lysine N-Methyltransferase/metabolism , Kidney Glomerulus/metabolism , Mesangial Cells/metabolism , Animals , Antibodies/pharmacology , Blotting, Western , Cyclin-Dependent Kinase Inhibitor p21/drug effects , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/metabolism , Diabetic Nephropathies/metabolism , Gene Expression Regulation , Glucose/pharmacology , In Vitro Techniques , Lysine , Male , Mesangial Cells/drug effects , Methylation , Promoter Regions, Genetic , Rats , Rats, Wistar , Transforming Growth Factor beta1/antagonists & inhibitorsABSTRACT
OBJECTIVE: To investigate the clinical and histopathological features of non-diabetic renal disease (NDRD) superimposed on diabetic nephropathy (DN) in northeastern Chinese patients with type 2 diabetes mellitus (T2D), and compare the changes with those of pure DN and isolated NDRD. METHODS: Single-center retrospective analysis based on medical records of 273 patients (172 men, mean age: 51.1 ± 12.4 years) with T2D who underwent renal biopsy between February 2000 and October 2015. All patients were diagnosed as cases of pure DN, isolated NDRD or NDRD superimposed on DN. RESULTS: Out of the 273 T2D patients, 68 (24.9 %) had DN, 175 (64.1 %) had NDRD, and 30 (11.0 %) had NDRD superimposed on DN. Idiopathic membranous nephropathy (IMN, 29.7 %) was the most common NDRD followed by IgA nephropathy (IgAN, 22.9 %), and hypertensive renal arteriolar sclerosis was the most common lesion in patients diagnosed as NDRD superimposed on DN. Patients with NDRD had a shorter duration of diabetes and lower frequencies of diabetic retinopathy (DR, 6.9 %) and renal failure (28.0 %), which is consistent with higher estimated glomerular filtration rates (eGFR) and lower systolic blood pressure (SBP). No significant between-group differences were observed with respect to proteinuria and hematuria. CONCLUSION: Renal biopsy is strongly recommended for T2D patients to distinguish DN, NDRD and NDRD superimposed on DN, especially in patients with no signs of DR. This approach may help in early diagnosis and treatment of NDRD and improve renal outcomes in northeastern Chinese T2D patients.
