PAR1 Inhibition Improves Renal Function, Attenuates Podocyte Calcium Dysregulation, and Alters Inflammatory Lipid Mediators in Diabetic Nephropathy

Diabetic nephropathy (DN) stands as the primary cause of end-stage renal failure. The pathological changes associated with DN, such as albuminuria and glomerular damage, result in progressive loss of renal function. Despite existing treatments, DN continues to worsen in many patients, requiring novel therapeutic strategies targeting disease progression mechanisms. Our recent studies have demonstrated that elevated levels of serine proteases during the progression of DN lead to overactivation of protease-activated receptor 1 (PAR1) signaling mechanisms. This overactivation drives excessive calcium influx in podocytes, resulting in the onset of albuminuria, perturbations in glomerular hemodynamics, and kidney damage. Therefore, pharmacological inhibition of PAR1 may blunt the effect of PAR1 signaling on DN progression. To test this hypothesis, we used a selective PAR1 antagonist Vorapaxar (SCH 530348, 10 mg/kg of diet). Vorapaxar is an FDA-approved medication used as antiplatelet therapy to reduce the risk of thrombotic cardiovascular events. 16-week-old male type 2 diabetic nephropathy (T2DN) rats were treated for 4 months to determine the effect of pharmacological systemic PAR1 inhibition on the development of DN. After 4 months of treatment, the glomerular filtration rate (GFR) was better preserved in the treated animals compared to the control group, which showed a decline (0.76 ± 0.19 vs 1.11 ± 0.29 mL/min/100g b.w., p=0.032, N≥6). The development of albuminuria was evident in both groups, confirming the progression of DN. However, a trend toward decline in the Alb/Cre ratio in the treated group was observed (12.4 ± 6.3 vs 8.1 ± 3.8, p=0.08, N≥6). Freshly isolated glomeruli from the vorpaxar-treated animals exhibit a significant decline in thrombin-induced calcium response and basal calcium levels within podocytes (240 ± 147 vs 145 ± 80 nM, p=0.035, n≥13, N≥6). Additionally, PAR1 inhibition influenced inflammation-resolution mediators in both the kidney and heart. In the kidney, Maresin Conjugates in Tissue Regeneration (MCTR1) were significantly upregulated, while hydroxy-docosahexaenoic acids (7-, 14-, and 17-HDHA) were downregulated. In the heart, significant downregulation was observed for Resolvine D4 (RvD4), Protectin D1 (PD1), and 17-HDHA. The inhibition of thrombin-induced calcium signaling and reduced basal calcium levels highlight a potential protective effect of PAR1 inhibition on podocytes. Changes in GFR may be linked to reduced glomerular damage, indicating that the structural integrity of the glomeruli is better maintained in treated animals. These findings point to PAR1 inhibition as a potential therapeutic strategy for protecting kidney function and modulating inflammatory and pro-resolving pathways in DN. The observed changes in lipid mediators and podocyte calcium dynamics suggest both direct and systemic effects, which may help mitigate the progression of kidney and heart complications commonly associated with diabetes. This work is supported by NIH grants R01 DK135644 (to A.S.) and R01 DK129227 (to A.S. and O.P.), and the Vascular Inflammation and Injury Training Program T32 HL160529 (to R.B.). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.