Novel Plasminogen Activator Inhibitor-1 Inhibitors Prevent Diabetic Kidney Injury in a Mouse Model

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, but no effective therapeutic strategy is available. Because plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a key factor in extracellular matrix (ECM) accumulation in diabetic nephropathy, this study examined the renoprotective effects of TM5275 and TM5441, two novel orally active PAI-1 inhibitors that do not trigger bleeding episodes, in streptozotocin (STZ)-induced diabetic mice. TM5275 (50 mg/kg) and TM5441 (10 mg/kg) were administered orally for 16 weeks to STZ-induced diabetic and age-matched control mice. Relative to the control mice, the diabetic mice showed significantly increased (p糖尿病肾病（Diabetic nephropathy）是全球范围内终末期肾病（end-stage renal disease）的首要致病原因，但目前尚无有效的治疗策略。鉴于纤溶酶原激活物抑制剂-1（PAI-1）在糖尿病肾病的细胞外基质（ECM）积聚过程中作为关键因子的作用日益受到认可，本研究考察了TM5275与TM5441这两种新型口服活性PAI-1抑制剂（且不会引发出血事件）在链脲佐菌素（STZ）诱导的糖尿病小鼠中的肾脏保护作用。研究中，对链脲佐菌素诱导的糖尿病小鼠及年龄匹配的对照组小鼠经口给予TM5275（50 mg/kg）与TM5441（10 mg/kg），持续给药16周。与对照组小鼠相比，糖尿病小鼠的相关指标显著升高（p