Praliciguat inhibits progression of diabetic nephropathy in ZSF1 rats and suppresses inflammation and apoptosis in human renal proximal tubular cells.

Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide (NO)-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In this study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy (DN). Praliciguat monotherapy did not affect hemodynamics. In contrast, enalapril monotherapy lowered blood pressure but did not attenuate proteinuria. Renal expression of genes in pathways involved in inflammation, fibrosis, oxidative stress, and kidney injury were lower in praliciguat-treated obese ZSF1 rats than in obese controls; fasting glucose and cholesterol were also lower with praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacologic effects on the kidneys, we studied praliciguat's effects on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTC). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein 1 in tumor necrosis factor α-challenged RPTC. Praliciguat treatment also attenuated transforming growth factor β-mediated apoptosis, changes to a mesenchymal-like cellular phenotype, and phosphorylation of SMAD3 in RPTC. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of DN, and its actions in human RPTC suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.