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Received for publication December 13, 2004.
Revised March 10, 2005.
Accepted for publication March 10, 2005.
-type I Receptor Kinase in Puromycin-Induced Nephritis
SB-525334, 6-[2-tert-butyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-quinoxaline, has been characterized as a potent and selective inhibitor of the transforming growth factor-
1 (TGF-1) receptor, activin receptor-like kinase (ALK5). The compound inhibited ALK5 kinase activity with an IC50 of 14.3 nM and was ~4-fold less potent as an inhibitor of ALK4 (IC50 = 58.5 nM). SB-525334 was inactive as an inhibitor of ALK2, ALK3, and ALK6 (IC50 >10,000 nM). In cell based assays, SB-525334 (1 µM), blocked TGF-1-induced phosphorylation and nuclear translocation of Smad2/3 in renal proximal tubule cells and inhibited TGF-1-induced increases in plasminogen activator inhibitor-1 (PAI-1) and procollagen-
1(l) mRNA expression in A498 renal epithelial carcinoma cells. In view of this profile, SB-525334 was used to investigate the role of TGF-1 in the acute puromycin aminononucleoside (PAN) rat model of renal disease, a model of nephritis-induced renal fibrosis. Orally administered doses of 1, 3 or 10 mg/kg/day of SB-525334 for 11 days produced statistically significant reductions in renal PAI-1 mRNA. Also, the compound produced dose dependent decreases in renal procollagen-1(l) and procollagen-1(lll) mRNA which reached statistical significance at the 10 mg/kg/day dose when compared to vehicle treated PAN controls. Further, PAN-induced proteinuria was significantly inhibited at the 10 mg/kg/day dose level. These results provide further evidence for the involvement of TGF-1 in the profibrotic changes that occur in the PAN model and for the first time demonstrate the ability of a small molecule inhibitor of ALK5 to block several of the markers that are predictive of fibrosis and renal injury in this model.
Key words:
ALK5, Extracellular matrix, Puromycin aminonucleoside, TGF-[beta]1, fibrosis, kidney
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