FP232
CG200745 ATTENUATES RENAL INJURY IN OBSTRUCTIVE NEPHROPATHY IN MICE

INTRODUCTION AND AIMS: Tubulointerstitial fibrosis is a common feature of kidney disease. Histone deacetylase(HDAC) inhibitors have been reported to attenuate progression of renal fibrosis in obstructed kidney. In this study, we investigated the effect of CG200745, a novel HDAC inhibitor, on development of renal fibrosis in a mice model of unilateral ureteral obstruction.

METHODS: To examine the effects of CG200745 in unilateral ureteral obstruction(UUO), C57BL6 male mice were divided into three groups: control, UUO, and CG200745(30mg/kg/day) treated UUO mice. CG 200745 was administered through drinking water for 1 week. We also treated human proximal tubular epithelial (HK-2) cells with CG200745(10uM) in the presence or absence of TGF-β1 (2 ng/mL).

RESULTS: At seventh day after UUO, kidney developed marked fibrosis as indicated by deposition of collagen and increased expression of α-smooth muscle actin (SMA) and fibronectin. Treatment with CG200745 attenuated these fibrotic responses. CG200745 treatment also suppressed UUO induced production of transforming growth factor-beta1 (TGF-beta) and phosphorylation of Smad-2/3. Treatment of CG200745 attenuated UUO-induced inflammation as indicated by decreased expression of heme oxygenase 1, F4/80, and mRNA expression of tumor necrosis factor alpha(TNF-alpha), monocyte chemotactic protein 1(MCP-1), intercellular adhesion molecule 1(ICAM-1) and vascular cell adhesion molecule 1(VCAM-1). Further, CG200745 attenuated phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) in UUO kidneys. In HK-2 cells, TGF-beta induced the expression of α-SMA and fibronectin, which were attenuated by CG200745 cotreatment.

CONCLUSIONS: These results demonstrate that CG200745, a novel HDAC inhibitor, have renoprotective effect by suppressing renal fibrosis and inflammation in UUO mice model.