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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Inhibition of Gene Markers of Fibrosis with a Novel Inhibitor of Transforming Growth Factor-β Type I Receptor Kinase in Puromycin-Induced Nephritis

Eugene T. Grygielko, William M. Martin, Christopher Tweed, Peter Thornton, John Harling, David P. Brooks and Nicholas J. Laping
Journal of Pharmacology and Experimental Therapeutics June 2005, 313 (3) 943-951; DOI: https://doi.org/10.1124/jpet.104.082099
Eugene T. Grygielko
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William M. Martin
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Christopher Tweed
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Peter Thornton
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John Harling
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David P. Brooks
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Nicholas J. Laping
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Abstract

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-β1 (TGF-β1) 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-β1-induced phosphorylation and nuclear translocation of Smad2/3 in renal proximal tubule cells and inhibited TGF-β1-induced increases in plasminogen activator inhibitor-1 (PAI-1) and procollagen α1(I) mRNA expression in A498 renal epithelial carcinoma cells. In view of this profile, SB-525334 was used to investigate the role of TGF-β1 in the acute puromycin aminonucleoside (PAN) rat model of renal disease, a model of nephritis-induced renal fibrosis. Orally administered doses of 1, 3, or 10 mg/kg/day SB-525334 for 11 days produced statistically significant reductions in renal PAI-1 mRNA. Also, the compound produced dose-dependent decreases in renal procollagen α1(I) and procollagen α1(III) mRNA, which reached statistical significance at the 10-mg/kg/day dose when compared with vehicle-treated PAN controls. Furthermore, PAN-induced proteinuria was significantly inhibited at the 10-mg/kg/day dose level. These results provide further evidence for the involvement of TGF-β1 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.

Footnotes

  • All research for this manuscript was supported by GlaxoSmithKline.

  • doi:10.1124/jpet.104.082099.

  • ABBREVIATIONS: TGF, transforming growth factor; ECM extracellular matrix; PAI-1, plasminogen activator inhibitor-1; ALK, activin receptor-like kinase; MAPK, mitogen-activated protein kinase; PAN, puromycin aminonucleoside; FBS, fetal bovine serum; RPTE, renal proximal tubule epithelial; SB-525334, 6-[2-tert-butyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-quinoxaline; GST, glutathione S-transferase; PBS, phosphate-buffered saline; RT, reverse transcriptase; PCR, polymerase chain reaction; SD, Sprague-Dawley; bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; MES, 4-morpholineethanesulfonic acid; ANOVA, analysis of variance.

    • Received December 10, 2004.
    • Accepted March 10, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 3
1 Sep 2022
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Inhibition of Gene Markers of Fibrosis with a Novel Inhibitor of Transforming Growth Factor-β Type I Receptor Kinase in Puromycin-Induced Nephritis

Eugene T. Grygielko, William M. Martin, Christopher Tweed, Peter Thornton, John Harling, David P. Brooks and Nicholas J. Laping
Journal of Pharmacology and Experimental Therapeutics June 1, 2005, 313 (3) 943-951; DOI: https://doi.org/10.1124/jpet.104.082099

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Inhibition of Gene Markers of Fibrosis with a Novel Inhibitor of Transforming Growth Factor-β Type I Receptor Kinase in Puromycin-Induced Nephritis

Eugene T. Grygielko, William M. Martin, Christopher Tweed, Peter Thornton, John Harling, David P. Brooks and Nicholas J. Laping
Journal of Pharmacology and Experimental Therapeutics June 1, 2005, 313 (3) 943-951; DOI: https://doi.org/10.1124/jpet.104.082099
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