sGC stimulator (BAY 41-8543) combined with PDE9 inhibitor (BAY 73-6691) reduces renal fibrosis in 5/6 nephrectomized rats.

Autor: Chen X; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Germany.; Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.; The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China., Delić D; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Germany.; Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Liu Y; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Germany.; Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany., Cao Y; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Germany.; Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany., Zhang Z; The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China., Wu H; The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China., Gaballa MMS; Department of Pathology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt.; Academy of Scientific Research & Technology, Cairo, Egypt., Klein T; Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Elitok S; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Germany.; Department of Nephrology and Endocrinology, Ernst von Bergmann Klinikum, Potsdam, Germany.; HMU - Health and Medical University, Potsdam, Germany., Krämer BK; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Germany.; European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, Germany., Hocher B; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Germany.; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China.; IMD Institut für Medizinische Diagnostik Berlin-Potsdam GbR, Berlin, Germany.
Jazyk: angličtina
Zdroj: Basic & clinical pharmacology & toxicology [Basic Clin Pharmacol Toxicol] 2025 Jan; Vol. 136 (1), pp. e14103. Date of Electronic Publication: 2024 Nov 09.
DOI: 10.1111/bcpt.14103
Abstrakt: Renal fibrosis is closely related to the prognosis of chronic kidney disease (CKD). The increase in cGMP reduces renal fibrosis. Soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) are key enzymes that maintain cGMP levels. BAY 41-8543 (1 mg/kg/day) and/or BAY 73-6691 (1 mg/kg/day) were used to treat 5/6 nephrectomized rats for 13 weeks. 5/6 Nephrectomy caused an increase in cystatin C, proteinuria and glomerulosclerosis and renal interstitial fibrosis. Neither sGC stimulation nor PDE9 inhibition alone improved kidney function and morphology, whereas BAY 41-8543 in combination with BAY 73-6691 attenuated renal interstitial fibrosis. This beneficial effect could not be explained by alterations in blood pressure and the renal immune system. BAY 41-8543 in combination with BAY 73-6691 had no effect on renal macrophage, CD4 + T-cell and CD8 + T-cell in the late-stage of 5/6 nephrectomy. RNA sequencing revealed BAY 41-8543 in combination with BAY 73-6691 down-regulated the expression of fibrosis-related genes such as Collagen Type I Alpha 1, Collagen Type III Alpha 1 Chain and Collagen Type XIV Alpha 1 Chain. sGC stimulator combined with PDE9 inhibitor attenuated renal fibrosis in 5/6 nephrectomized rats by down-regulating fibrosis-related gene expression. This novel approach of using low-dose combination therapies to minimize side effects while maintaining therapeutic efficacy offers a promising strategy for the treatment of CKD.
(© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)
Databáze: MEDLINE
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