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Renal and cardiac effects of the PDE9 inhibitor BAY 73–6691 in 5/6 nephrectomized rats

  • Integrative Physiology
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Abstract

It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3′,5′-cyclic guanosine monophosphate (cGMP) degradation. 5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73–6691) on the heart and kidney. Two doses of BAY 73–6691 (1 mg/kg/day and 5 mg/kg/day) were given for 95 days. The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95 days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73–6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)—protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways. Two dosages of the PDE9 inhibitor BAY 73–6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.

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Acknowledgements

China Scholarship Council supported X.C. and Y.C.

Author information

Author notes

  1. Xin Chen, Denis Delić, and Yaochen Cao contributed equally to this work.

Authors and Affiliations

  1. Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany

    Xin Chen, Denis Delić, Yaochen Cao, Ahmed A. Hasan, Bernhard K. Krämer & Berthold Hocher

  2. Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany

    Xin Chen & Yaochen Cao

  3. The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China

    Xin Chen, Zeyu Zhang, Hongwei Wu & Lianghong Yin

  4. Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397, Biberach, Germany

    Denis Delić

  5. Faculty of Veterinary Medicine, Benha University, Toukh, Egypt

    Mohamed M. S. Gaballa

  6. European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

    Bernhard K. Krämer

  7. Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach, Germany

    Thomas Klein

  8. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Xin Shi, Ben He & Linghong Shen

  9. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China

    Berthold Hocher

  10. IMD Institut Für Medizinische Diagnostik Berlin-Potsdam GbR, Berlin, Germany

    Berthold Hocher

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  1. Xin Chen
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Contributions

B.Hocher conceived and designed the study. X.C., Y.C., Z.Z., H.W. and L.Y. performed the animal experiment. X.C., Y.C., D.D., A.A.H., M.MS.G., T.K., X.S. and L.S. performed the biological and histological analyses and statistical evaluation. X.C. analyzed the final data set and wrote the initial manuscript. L.Shen, B.He, B.Hocher and B.K.Krämer supervised and significantly amended the manuscript. All authors contributed to revising and editing of the manuscript and approved the final version of the manuscript.

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Correspondence to Berthold Hocher.

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Chen, X., Delić, D., Cao, Y. et al. Renal and cardiac effects of the PDE9 inhibitor BAY 73–6691 in 5/6 nephrectomized rats. Pflugers Arch - Eur J Physiol 476, 755–767 (2024). https://doi.org/10.1007/s00424-024-02915-2

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