NDT Advance Access published online on December 27, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl668
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Enhancement of epithelial sodium channel expression in renal cortical collecting ducts cells by advanced glycation end products
1Graduate Institute of Clinical Medical Sciences, Chang Gung University and 2Kidney Research Institute, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
Correspondence and offprint requests to: Cheng-Chieh Hung, MD, PhD, Kidney Research Institute and Department of Nephrology, Chang Gung Memorial Hospital, 5, Fu-Shing St., Kueishan, Taoyuan 333, Taiwan. Email: cchung9651{at}yahoo.com
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Abstract |
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Background. The epithelial sodium channel (ENaC) is a complex, and the 
ENaC subunit has a crucial role in sodium uptake induced by aldosterone in the distal nephron. Although experimental animal models of diabetes have demonstrated up-regulation of ENaC expression in renal cortical collecting duct (CCD) cells, the molecular mechanism remains unclear. Advanced glycation end products (AGEs) are by-products of long-term hyperglycaemia and comprise a significant pathogenic factor in diabetic nephropathy. We hypothesize that AGEs play a role in regulating ENaC gene expression.
Methods. Mouse CCD cells (mpkCCDcl4) were cultured with AGE to determine the effects of AGE on ENaC expression and sodium uptake. Gene expressions of ENaC were measured by real-time PCR and sodium uptake was measured with fluorescent dye as a sodium indicator (SBFI-AM). This study analysed mitogen-activated protein kinases signalling pathways by western blotting. Cells co-transfected with plasmids of the ENaC promoter carrying a luciferase reporter and plasmids expressing wild-type or mutant serum- and glucocorticoid-induced kinase 1 (Sgk1) mRNA were stimulated with AGE to identify the signalling pathway.
Results. The AGEs, stimulated in a time- and dose-dependent manner, enhanced ENaC mRNA expression and sodium uptake in mpkCCDcl4 cells. The AGEs also significantly stimulated Sgk1 mRNA and Sgk1 activity in a time- and dose-dependent manner. Co-transfected with plasmid expressing mutant Sgk1 significantly limited stimulated ENaC promoter-driven luciferase activity by AGEs in mpkCCDcl4 cells.
Conclusion. Experimental results indicate that AGEs induced ENaC expression and increased sodium uptake in renal CCD cells. The mechanism through which AGEs activate ENaC expression may be via activation of Sgk1 in mpkCCDcl4 cells.
Keywords: advanced glycation end products; cortical collecting duct cells; diabetic nephropathy; epithelial sodium channel; serum- and glucocorticoid-induced kinase
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