Palfrey Henry A, Goorani Samaneh, Mishra Abhishek, Hye Khan Md Abdul, Acharya Baku, Frett Brendan, Imig John D
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
J Pharmacol Exp Ther. 2025 Aug;392(8):103644. doi: 10.1016/j.jpet.2025.103644. Epub 2025 Jun 25.
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.
肾纤维化是慢性肾脏病发展至终末期肾病的常见过程，其病因是多方面的。肾纤维化的有效治疗需要能同时针对多种分子机制的策略。在本研究中，我们研究了新型转化生长因子-β受体（TGF-βR）1和丝裂原活化蛋白4激酶（MAP4K）4双重抑制剂TK-850的预防和干预抗纤维化作用。使用8至10周龄的雄性和雌性C57Bl/6小鼠评估TK-850的抗纤维化潜力，这些小鼠接受单侧输尿管梗阻（UUO）手术以诱导肾纤维化。将啮齿动物进行UUO手术，并在UUO前7天或UUO后3天腹腔注射TK-850（每天20mg/kg）。对侧肾脏作为对照。UUO术后10天收集肾脏和血液进行组织病理学和生化分析。肾脏羟脯氨酸水平是胶原蛋白含量和纤维化的标志物，在所有组中均因UUO而升高；然而，TK-850的预防性和干预性给药有效降低了这些水平，表明其减轻肾纤维化的潜力。基因阵列数据显示几种促纤维化基因上调，特别是促进细胞外基质积累的Timp1。预防性或干预性TK-850给药降低了UUO小鼠中Timp1的表达。UUO小鼠肾间质胶原蛋白增加，而预防性和干预性TK-850可使其减少。值得注意的是，TK-850的预防性和干预性给药均未影响最终体重或导致任何死亡。总体而言，这些数据提供了概念验证，即新型双效TGF-βR1/MAP4K4抑制剂TK-850是一种肾抗纤维化药物。意义声明：新型双转化生长因子-β受体1/丝裂原活化蛋白4激酶4抑制剂TK-850通过降低羟脯氨酸和金属蛋白酶组织抑制剂1水平，在单侧输尿管梗阻小鼠模型中减轻肾纤维化，而不影响体重或死亡率，支持其治疗潜力。
