Effects of soluble guanylate cyclase stimulator on renal function in ZSF-1 model of diabetic nephropathy

• Published in: PloS one 2022-01, Vol.17 (1), p.e0261000
• Main Authors: Hu, Lufei, Chen, Yinhong, Zhou, Xiaoyan, Hoek, Maarten, Cox, Jason, Lin, Ken, Liu, Yang, Blumenschein, Wendy, Grein, Jeff, Swaminath, Gayathri
• Format: Article
• Language: English
• Subjects: Albumins; Analysis; Animals; Bioavailability; Biology and Life Sciences; Blood pressure; Blood Pressure - drug effects; Care and treatment; CHO Cells; Chronic kidney failure; Creatinine; Cricetulus; Cyclic GMP; Cyclic guanylic acid; Development and progression; Diabetes; Diabetes mellitus; Diabetic nephropathies; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - physiopathology; Diabetic nephropathy; Diagnosis; Disease Models, Animal; Dosage and administration; Drug dosages; Drug Therapy, Combination; Enalapril; Enalaprilat; Enalaprilat - administration & dosage; Enalaprilat - pharmacology; Enzyme Activators - administration & dosage; Enzyme Activators - pharmacology; Enzymes; Epidermal growth factor receptors; Excretion; Gene Expression Profiling; Glomerular filtration rate; Guanylate cyclase; Heart failure; Heart rate; Histopathology; Hypertension; Kidney diseases; Kidney Function Tests; Laboratory animals; Male; Medicine and health sciences; Metabolism; Nephropathy; Nitric oxide; Nitric Oxide - metabolism; Obesity; Oxidative Stress; Pharmacokinetics; Pilot Projects; Proteinuria; Rats; Renal function; Risk factors; Signal transduction; Signal Transduction - drug effects; Signaling; Soluble Guanylyl Cyclase - metabolism; Stimulators; Telemetry; Treatment Outcome
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0261000

Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC stimulator Compound 1 can enhance NO signaling, reduce proteinuria in a diabetic nephropathy preclinical model with diminished NO bioavailability and increased oxidized sGC. Therefore, we evaluated the effect of sGC stimulator Compound 1 on the renal effect in obese ZSF1 (ZSF1 OB) rats. The sGC stimulator Compound 1, the standard of care agent Enalapril, and a combination of Compound 1 and Enalapril were administered chronically to obese ZSF1 rats for 6 months. Mean arterial pressure, heart rate, creatinine clearance for glomerular filtration rate (eGFR), urinary protein excretion to creatinine ratio (UPCR), and urinary albumin excretion ratio (UACR) were determined during the study. The histopathology of glomerular and interstitial lesions was assessed at the completion of the study. While both Compound 1 and Enalapril significantly reduced blood pressure, the combination of Compound 1 and Enalapril normalized blood pressure levels. Compound 1 improved eGFR and reduced UPCR and UACR. A combination of Enalapril and Compound 1 resulted in a marked reduction in UPCR and UACR and improved GFR. The sGC stimulator Compound 1 as a monotherapy slowed renal disease progression, and a combination of the sGC stimulator with Enalapril provided greater renal protection in a rodent model of diabetic nephropathy.