Abstract
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 < 0.05) plasma glucose and creatinine levels, urinary albumin excretion, kidney-to-bodyweight ratios, glomerular volume, and fractional mesangial area. Markers of fibrosis and inflammation along with PAI-1 were also upregulated in the kidney of diabetic mice, and treatment with TM5275 and TM5441 effectively inhibited albuminuria, mesangial expansion, ECM accumulation, and macrophage infiltration in diabetic kidneys. Furthermore, in mouse proximal tubular epithelial (mProx24) cells, both TM5275 and TM5441 effectively inhibited PAI-1-induced mRNA expression of fibrosis and inflammation markers and also reversed PAI-1-induced inhibition of plasmin activity, which confirmed the efficacy of the TM compounds as PAI-1 inhibitors. These data suggest that TM compounds could be used to prevent diabetic kidney injury.
Highlights
Diabetic kidney disease is the leading cause of end-stage renal disease worldwide and an independent risk factor for cardiovascular morbidity and mortality [1]
Diabetic kidney injury is characterized by albuminuria, a reduced glomerular filtration rate, and excessive extracellular matrix (ECM) deposition, which leads to glomerular mesangial expansion and tubulointerstitial fibrosis [3,4,5]
The plasma glucose level in diabetic mice was not affected by treatment with either TM5275 (50 mg/kg) or TM5441 (10 mg/kg) (Table 1)
Summary
Diabetic kidney disease is the leading cause of end-stage renal disease worldwide and an independent risk factor for cardiovascular morbidity and mortality [1]. PAI-1 Inhibitors Protect Mice against Diabetic Nephropathy does not stop the development and progression of kidney injury in diabetes [2]. PAI-1 has emerged as a powerful fibrogenic mediator in kidney diseases, including diabetic nephropathy [8, 9] and anti-Thy-1-antibodymediated glomerulonephritis [10]. PAI-1 deficiency attenuates diabetic nephropathy [12,13,14], and disruption of the PAI-1 gene markedly attenuates thrombosis and fibrosis in mice [12, 15, 16]. Inhibition of PAI-1 gene expression might exert critical renoprotective effects [17], and the discovery of specific PAI-1 antagonists might yield new therapeutic approaches [18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
