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      Endothelial ANP/GC-A signaling is critically involved in acute ANP-induced stimulation of natriuresis

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      cGMP: Generators, Effectors and Therapeutic Implications Conference
      cGMP: Generators, Effectors and Therapeutic Implications
      June 28-30, 2024
      Natriuretic peptides, ANP, atrial natriuretic peptide, GC-A, NPR-A, renal function, natriuresis, endothelium
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            Abstract

            Question: Cardiac atrial (ANP) and B-type natriuretic peptide (BNP) are centrally involved in maintaining blood pressure by regulating vascular tone, endothelial permeability and renal sodium/water excretion. These physiological effects are mediated by the membrane-bound guanylate cyclase-A (GC-A). Despite the clear relevance of NP-signaling for kidney function, it is unclear which cell types mediate these effects and if renal microvessels play a role. Methods: To identify renal target cells of NPs we performed systematical expression analysis of NP receptors in mouse kidneys using mRNA in-situ hybridization. The results led us to investigate the function of isolated perfused kidneys from mice with tamoxifen-induced endothelium-restricted deletion of GC-A (Cdh5-Cre/GC-Aflox/flox). Results: In mouse kidneys, podocytes and intrarenal blood vessels express GC-A at high abundance, while no expression was detectable in the tubular system. In the renal medulla, marked expression of GC-A was found in endothelial cells of peritubular capillaries. Infusion of ANP induced a concentration-dependent increase in diuresis, natriuresis and renal blood flow in isolated perfused kidneys. Endothelium-restricted knockout of GC-A reduced total renal GC-A expression by approximately 50% and abolished the natriuretic response to 100 pM ANP, while enhancing the ANP-induced increase in renal blood flow. In addition, the kidneys of knockout mice have a higher weight and lower mRNA expression of genes associated with endothelial barrier function. Conclusion: Endothelial GC-A signaling is critically involved in the ANP-induced increase in natriuresis and diuresis. The surprising finding that endothelial GC-A deletion prevents diuretic while augmenting vasodilating ANP effects directs our ongoing studies.

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            Author and article information

            Conference
            cGMP: Generators, Effectors and Therapeutic Implications Conference
            27 March 2024
            Affiliations
            [1 ] Institute of Physiology, University of Regensburg, Regensburg, Germany ( https://ror.org/01eezs655)
            [2 ] Institute of Physiology, University of Würzburg, Würzburg, Germany ( https://ror.org/00fbnyb24)
            Author notes
            Author information
            https://orcid.org/0009-0007-9507-6049
            Article
            10.14293/CGMP.24000070.v1
            decea160-d28e-49ea-9424-9ce2d857bb59

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

            cGMP: Generators, Effectors and Therapeutic Implications
            11
            Lübeck
            June 28-30, 2024
            History
            : 27 March 2024
            Categories

            The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
            Molecular medicine,Anatomy & Physiology,Molecular biology,Nephrology,Life sciences
            Natriuretic peptides,ANP,atrial natriuretic peptide,GC-A,NPR-A,renal function,natriuresis,endothelium

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