The renal transport function was assessed by the uptake of para-aminohippurate IWR-1 price (PAH) mediated organic anion transporters 1 (rOat1) and 3 (rOat3), using renal cortical slices. These two transporters were mainly expressed in renal proximal tubules and play important role for renal secretory process. Results: Comparing to T2DM, CGE supplemented

rats had significantly improved hyper-glycemia, hypertriglyceridemia, and insulin resistance. The uptake of PAH mediated by Oat1 and 3 functions in renal slices was not different among experimental groups. Interestingly, CGE blunted sodium nitroprusside-induced impairment of PAH uptake in T2DM rats. This data also correlated with the levels of NO accumulation in renal cortical tissues. Conclusion: These findings indicated that CGE has anti-diabetic effect and prevents diabetic nephropathy partly through nitrosative stress

ABT-263 molecular weight pathway. HASEGAWA KAZUHIRO, WAKINO SHU, HAYASHI KOICHI, ITOH HIROSHI Department of Nephrology, Keio University, Tokyo, Japan Introduction: Sirtuin 1 (Sirt1), a NAD-dependent deacetylase with positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. Among various renal cells, we previously reported that proximal tubular Sirt1 plays pivotal roles (Hasegawa K, BBRC 2008, JBC 2010). Sirt1 is also known to have protective effects against diabetic damages in liver or pancreas. However, a correlation between renal Sirt1 and diabetic kidney damages has not been investigated. Therefore, we aim to investigate the role of Sirt1 in diabetic nephropathy (DN). Methods and Results: We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria, and, thereafter, Sirt1 in podocytes (Pods) was downregulated in DN mice including both streptozotocin-induced and obese (db/db) mice. Then, we created PT-specific Sirt1 transgenic (Tg) and conditional knockout (CKO) mice to examine the role of PT’s Sirt1. Sirt1 Tg prevented and CKO aggravated Sirolimus supplier glomerular changes

and albuminuria that occured in diabetes, respectively. Non-diabetic CKO mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. We also observed that reduced PT’s Sirt1 in DN decreased NMN (Nicotinamide Mono Nucleotide, a key intermediate of Sirt1-related nicotinic acid metabolism) led to decreasing Pod’s Sirt1. Reduced Sirt1 increased Claudin-1, a tight junction protein, in Pods by an epigenetic mechanism whereby decreased Pod’s Sirt1 inactivated Dnmt1 leading to reduced CpG methylation of Claudin-1 gene, which contributed to increased Claudin-1 expression and albuminuria. Intriguingly, Claudins are generally known to strengthen the epithelial barrier, but we novely showed that overexpression of Claudin-1 in Pods increased glomerular permeability by activating β-catenin–Snail pathway.