Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on renal fibrosis in unilateral ureteral obstruction in rats.
Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. One morphological characteristic of CAN is renal interstitial fibrosis. Mycophenolate mofetil (MMF), the inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, has been reported to attenuate the progression of renal interstitial fibrosis. However, the question of whether the newly synthesized IMPDH inhibitors with structures different from MMF have an antifibrotic effect remains unanswered. We evaluated the antifibrotic effects of BMS-566419, a chemically synthesized IMPDH inhibitor, using an experimental rat model, unilateral ureteral obstruction (UUO), in comparison with those of MMF. Expression levels of monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta1 (TGF-β1), which play important roles in UUO-induced renal fibrosis, were also investigated to determine the mechanism by which BMS-566419 affects the progression of renal fibrosis. After 14 days of UUO, interstitial fibrosis was frequently observed in the renal cortex of rats administered vehicle control. BMS-566419 by oral administration showed a significant and dose-dependent suppressive effect on UUO-induced renal fibrosis in histopathological experiments. BMS-566419 treatment also decreased collagen content, as indicated by hydroxyproline concentration, and the expression of collagen type 1 mRNA. BMS-566419 also decreased the expression of mRNA for both MCP-1 and TGF-β1. The antifibrotic effects of treatment with BMS-566419 at 60 mg/kg seemed comparable to those with MMF at 40 mg/kg. These results suggest that BMS-566419 and other chemically synthesized IMPDH inhibitors have beneficial pharmacological effects similar to those of MMF, and are potential pharmaceutical candidates in the treatment of fibrotic renal disease, including CAN.
Nakanishi
Tomonori
T
Pharmacology Research Laboratories, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan. tomonori.nakanishi@jp.astellas.com
Morokata
Tatsuaki
T
Noto
Takahisa
T
Kubo
Kaori
K
Umeno
Hitomi
H
Kinugasa
Fumitaka
F
Eikyu
Yoshiteru
Y
Kozuki
Yoshihiro
Y
Seki
Nobuo
N
D000166:Acridines / Q000627:therapeutic use*; D000818:Animals; D018932:Chemokine CCL2 / Q000032:analysis; D002908:Chronic Disease; D003094:Collagen / Q000032:analysis; D005355:Fibrosis; D006909:Hydroxyproline / Q000032:analysis; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007672:Kidney Cortex / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D014517:Ureteral Obstruction / Q000150:complications*
D000166:Acridines; D018932:Chemokine CCL2; C523435:N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2-fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide; D010879:Piperazines; D053773:Transforming Growth Factor beta1; D003094:Collagen; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D006909:Hydroxyproline