MPS 13-07 EPIGENETIC CHANGE IN GLOMERULAR PODOCYTES OF PROTEINURIC CKD PATIENTS WITH ANGIOTENSIN RECEPTOR BLOCKER (ARB) TREATMENT

Abstract

Objective: Proteinuria is a central component of chronic kidney disease, and an independent risk factor for cardiovascular disease. Recently we have reported that Kruppel-like Factor 4 (KLF4) is expressed in kidney podocytes and decreased in glomerular diseases, which leads to methylation of the nephrin promoter, decreased nephrin expression and proteinuria (J Clin Invest 2014). Moreover we have shown that treatment of angiotensin receptor blocker (ARB) reduces methylation of the nephrin promoter in murine glomeruli of adriamycin nephropathy model with recovery of KLF4 expression and a decrease in proteinuria. In this study, we examined the expression of KLF4 and epigenetic changes in human glomerular diseases. Design and Method: we obtained renal biopsy samples from patients with proteinuric glomerular diseases diagnosed as minimal change disease (MCD, n = 9), focal segmental glomerulosclerosis (FSGS, n = 8) and diabetic nephropathy (DN, n = 8) compared with controls (n = 8). We performed immunofluorescence staining and methylation specific PCR method with the nephrin promoter region using laser-microdissected glomerular samples. Results: We confirmed decreased KLF4 expression in glomerular diseases as previously reported. Nephrin expression in patients with FSGS and DN was decreased. It is also revealed that unmethylated level of the nephrin promoter adjusted by podocyte number was reduced in glomerular diseases, and showed significant correlation to nephrin expression. KLF4 expression in ARB-treated patients was higher than in patients without ARB treatment. Unmethylated level of the nephrin promoter adjusted by podocyte number showed a marginal increase (p = 0.12) in ARB-treated patients. Conclusions: These results suggest that angiotensin II can modulate epigenetic regulation in podocytes and ARB inhibits these actions in part via KLF4 in human proteinuic kidney diseases. This study provides a new concept that renin-angiotensin system blockade can exerts therapeutic effects through epigenetic modulation of the kidney gene expression.