Prevention of renal interstitial fibrosis via histone deacetylase inhibition in rats with unilateral ureteral obstruction.
Acute rejection following renal transplantation has become manageable with the introduction of calcineurin inhibitors, FK506 and cyclosporine A. However, chronic allograft dysfunction accompanied by renal interstitial fibrosis, which induces graft loss, remains unresolved. Here, we evaluated the effect of FR276457, a pan-histone deacetylase (HDAC) inhibitor, on interstitial fibrosis in the injured kidneys of a rat model of unilateral ureteral obstruction. The injured kidneys, harvested on Day 14 following the operation, showed progression of interstitial fibrosis, increases of hydroxyproline contents, and mRNA expression of collagen type Ialpha1 and monocyte chemotactic protein 1 (MCP-1). However, these changes were found to be prevented with daily oral administration of FR276457. In addition, given that MCP-1 is believed to contribute to progressive fibrosis, we investigated the direct effect of FR276457 on MCP-1 production by activated THP-1 cells in vitro. Results showed that FR276457 administration decreased MCP-1 production in these cells in a concentration-dependent manner. Findings from the present study suggested that a pan-HDAC inhibitor may exert a prophylactic effect against renal interstitial fibrosis by inhibiting MCP-1 production.
Kinugasa
Fumitaka
F
Department of Applied Pharmacology 1, Applied Pharmacology Research Laboratories, Astellas Pharma Inc, Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan. fumitaka.kinugasa@jp.astellas.com
Noto
Takahisa
T
Matsuoka
Hideaki
H
Urano
Yasuharu
Y
Sudo
Yuji
Y
Takakura
Shoji
S
Mutoh
Seitaro
S
D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000517:prevention & control*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D009395:Nephritis, Interstitial / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014517:Ureteral Obstruction / Q000188:drug therapy*
D018932:Chemokine CCL2; C532215:FR276457; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids