Prevention of renal interstitial fibrosis via histone deacetylase inhibition in rats with unilateral ureteral obstruction

• Published in: Transplant immunology Vol. 23; no. 1; pp. 18 - 23
• Main Authors: Kinugasa, Fumitaka, Noto, Takahisa, Matsuoka, Hideaki, Urano, Yasuharu, Sudo, Yuji, Takakura, Shoji, Mutoh, Seitaro
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2010
• Subjects: Allergy and Immunology; Animals; Cell Line, Tumor; Chemokine CCL2 - antagonists & inhibitors; Chemokine CCL2 - metabolism; Disease Models, Animal; Fibrosis - prevention & control; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors - therapeutic use; Hydroxamic Acids - therapeutic use; Kidney - pathology; Kidney Transplantation; Male; Nephritis, Interstitial - prevention & control; Rats; Rats, Sprague-Dawley; Renal interstitial fibrosis; Unilateral ureteral obstruction; Ureteral Obstruction - drug therapy; Unilateral ureteral obstruction; Renal interstitial fibrosis; Histone deacetylase inhibitor
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2010.02.003

Abstract 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 Iα1 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.