pai-039 and Inflammation

Plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a mediator in extracellular matrix (ECM) accumulation in diabetic nephropathy. Previous studies have implicated PAI-1 in adipose tissue (AT) expansion, while also contributing to insulin resistance. As inflammation is also known to occur in perirenal AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model, PAI-1 contributes to macrophage-mediated inflammation and diabetic nephropathy. The HFD mice showed increased expression of PAI-1 in perirenal fat and also displayed increased fat weight and macrophage numbers. We found that the macrophage polarization, proinflammatory macrophage-M1-phenotype, including CD11c, IL-6, and monocyte chemoattractant protein-1, were increased by an HFD and decreased by either the genetic depletion of PAI-1 or treatment with the PAI-1 inhibitor, PAI-039. Similarly, an enhanced anti-inflammatory M2-phenotype, including CD206 and IL-10, was accompanied by either the genetic deletion of PAI-1 or PAI-039 treatment. Furthermore, the inhibition of PAI-1 reduced HFD-induced renal histological lesions and abated profibrotic/extracellular-matrix protein. Collectively, our findings provide support that PAI-1 contributes to the development of inflammation in perirenal fat and correlates with the development of diabetic nephropathy in HFD-induced obesity.

Topics: Adipose Tissue; Animals; Diabetic Nephropathies; Diet, High-Fat; Glomerular Filtration Rate; Indoleacetic Acids; Inflammation; Kidney; Macrophages; Mice; Mice, Knockout; Obesity; Serpin E2

This study aimed to evaluate a small-molecule PAI-1 inhibitor (PAI-039; tiplaxtinin) in a rodent stenosis model of venous thrombosis in a two-phase experiment. Phase 1 determined the efficacy of tiplaxtinin against Lovenox (LOV), while phase 2 determined the dose-dependent efficacy. For both phases, drug treatment began 24 hours after surgically induced venous thrombosis and continued for four days. Phase 1 animals (n = 24) receiving low-dose (LD; 1 mg/kg oral gavage) PAI-1 inhibitor demonstrated a 52% decrease in thrombus weight (TW) versus controls (p < 0.05) with significant reductions in active plasma PAI-1, while the high-dose (HD; 10 mg/kg oral gavage) group demonstrated a 23% reduction in TW versus controls. Animals treated subcutaneously with LOV (3 mg/kg) showed a 39% decrease in TW versus controls (p < 0.05). Coagulation tests (aPTT and TCT) were significantly different in LOV compared to PAI-1 inhibitor groups. PAI-039 treatment was also associated with significantly increased return of inferior vena cava blood flow four days post-thrombosis versus controls (p < 0.05). In phase 2 (n = 30), TW was reduced from the 0.5 mg/kg to 5 mg/kg experimental groups, with the 10 mg/kg group demonstrating a paradoxical increase. The 5 mg/kg group showed statistically significant decreases in TW versus controls after four treatment days (p < 0.05). This is the first study to demonstrate dose related effects of PAI-039 on increasing thrombus resolution and inferior vena cava blood flow without adverse effects on anti-coagulation in a rat stenosis model of venous thrombosis.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Enoxaparin; Fibrosis; Indoleacetic Acids; Inflammation; Male; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Tunica Intima; Vena Cava, Inferior; Venous Thrombosis