Transforming growth factor β receptor 1 and mitogen-activated protein 4 kinase 4 dual inhibitor, TK-850, reduces renal fibrosis in unilateral ureteral-obstructed mice.

Abstract

Renal fibrosis is a common progression from chronic kidney disease to end-stage renal disease, and its causes are multifactorial. Effective treatment for renal fibrosis requires strategies that address various molecular mechanisms simultaneously. In this study, we investigated the preventive and interventional anti-fibrotic effects of TK-850, a novel dual inhibitor of transforming growth factor-β receptor (TGF-βR)1 and mitogen-activated protein 4 kinase (MAP4K)4. The antifibrotic potential of TK-850 was evaluated using 8-10-week-old male and female C57Bl/6 mice that were subjected to unilateral ureteral obstruction (UUO) surgery to induce renal fibrosis. Rodents were subjected to UUO and were administered TK-850 (20 mg/kg per day intraperitoneally) 7 days before or 3 days following UUO. The contralateral kidneys served as the control. Kidneys and blood were collected 10 days post-UUO for histopathologic and biochemical analyses. Kidney hydroxyproline levels, a marker for collagen content and fibrosis, increased by UUO in all groups; however, TK-850 preventive and interventional administration effectively reduced these levels, indicating its potential to mitigate renal fibrosis. Gene array data demonstrated upregulation of several profibrotic genes, notably Timp1, which promote extracellular matrix accumulation. Preventive or interventional TK-850 administration reduced Timp1 expression in UUO mice. Renal interstitial collagen increased in UUO mice, and it was reduced by preventive and interventional TK-850. Notably, neither preventive nor interventional administration of TK-850 affected the terminal body weight or caused any mortality. Overall, these data provide proof of concept that the novel dual-acting TGF-βR1/MAP4K4 inhibitor, TK-850, is a renal antifibrotic agent. SIGNIFICANCE STATEMENT: TK-850, a novel dual transforming growth factor-β receptor 1/ mitogen-activated protein 4 kinase 4 inhibitor, reduces renal fibrosis in a unilateral ureteral obstruction mouse model by lowering hydroxyproline and tissue inhibitor of metalloproteinase 1 levels without impacting body weight or mortality, supporting its therapeutic potential.