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

Author:

Liu Guang1,Shea Courtney M.1,Jones Juli E.1,Price Gavrielle M.2,Warren William3,Lonie Elisabeth3,Yan Shu4,Currie Mark G.5,Profy Albert T.6,Masferrer Jaime L.1,Zimmer Daniel P.1ORCID

Affiliation:

1. Department of Pharmacology, Cyclerion Therapeutics, Cambridge, Massachusetts

2. Department of Medical Writing, Cyclerion Therapeutics, Cambridge, Massachusetts

3. Department of Analytical Pharmacology, Ironwood Pharmaceuticals, Cambridge, Massachusetts

4. Department of Discovery Informatics, Cyclerion Therapeutics, Cambridge, Massachusetts

5. Department of Research Management, Cyclerion Therapeutics, Cambridge, Massachusetts

6. Department of Development Management, Cyclerion Therapeutics, Cambridge, Massachusetts

Abstract

Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In the present study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy. 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 was lower in praliciguat-treated obese ZSF1 rats than in obese control rats; fasting glucose and cholesterol were also lower with praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacological effects on the kidneys, we studied the effects of praliciguat on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTCs). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein-1 in tumor necrosis factor-α-challenged RPTCs. Praliciguat treatment also attenuated transforming growth factor-β-mediated apoptosis, changes to a mesenchyme-like cellular phenotype, and phosphorylation of SMAD3 in RPTCs. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of diabetic nephropathy, and its actions in human RPTCs suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.

Publisher

American Physiological Society

Subject

Physiology

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