The knock-out of paracingulin attenuates hypertension through modulation of kidney ion transport

Article Article scientifique Article The knock-out of paracingulin attenuates hypertension through modulation of kidney ion transport eng 2025-04-09 author Rouaud Florian Department of Molecular and Cellular Biology, Faculty of Sciences, University of Geneva, Geneva. 861568 Département de biologie moléculaire et cellulaire (MOCEL) author Meens Merlijn 0000-0002-5483-951X Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Research Office, Faculty of Health, Medicine and Life Sciences, Maastricht, the Netherlands. 767675 author Yvon Raphaël Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 416762 Département de physiologie cellulaire et métabolisme (PHYME) author Hautefort Aurélie Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 896281 author Legouis David 0000-0002-2924-9737 Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Division of Intensive Care, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland. 883952 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Mean Isabelle 0000-0002-3453-0507 Department of Molecular and Cellular Biology, Faculty of Sciences, University of Geneva, Geneva. 682897 Département de biologie moléculaire et cellulaire (MOCEL) author Jond Lionel Department of Molecular and Cellular Biology, Faculty of Sciences, University of Geneva, Geneva. 96467 Département de biologie moléculaire et cellulaire (MOCEL) author Maillard Marc Aimé Charles 0000-0001-6428-0046 Department of Nephrology and Hypertension, Faculty of Medicine, University of Lausanne, Switzerland. 54695 author Kwak Brenda 0000-0003-0015-0044 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 113350 Département de pathologie et immunologie (PATIM) author Moll Solange 0000-0002-1809-9884 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 28349 Département de pathologie et immunologie (PATIM) author De Seigneux Matthey Sophie 0000-0002-4243-366X Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 105798 Département de médecine (DEMED) author Feraille Eric 0000-0003-1656-8365 Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 27356 Département de physiologie cellulaire et métabolisme (PHYME) author Citi Sandra 0000-0002-6537-4818 Department of Molecular and Cellular Biology, Faculty of Sciences, University of Geneva, Geneva. 116085 Département de biologie moléculaire et cellulaire (MOCEL) 10.1152/ajprenal.00271.2024 40204428 1522-1466 https://journals.physiology.org/doi/abs/10.1152/ajprenal.00271.2024 Hypertension is a major risk factor for human morbidity and mortality, and the junctional protein paracingulin (CGNL1, JACOP) is required for development of hypertension in a Dahl salt-sensitive rat model and is linked to human hypertension in genome-wide association studies. However, the mechanism through which CGNL1 may regulate hypertension is unknown. Here we address this question using a mouse model, where hypertension is induced by unilateral nephrectomy and angiotensin II infusion (N+A model). Although untreated WT and CGNL1-KO mice showed similar blood pressure, the N+A protocol induced hypertension in WT mice but not in CGNL1-KO mice. We show by immunolocalization and transcriptomic analysis that CGNL1 is expressed throughout the kidney tubules and in endothelium of blood vessels, but not in smooth muscle. The (N+A) protocol induced decreased potassium urinary excretion in wild-type (WT), but not CGNL1-KO mice. Immunoblot analysis shows that the KO of CGNL1 blunted the (N+A)-induced changes in the expression levels and activation of tubular ion transporters, including the Na/H exchanger 3 (NHE3) and the thiazide-sensitive Na-Cl cotransporter (NCC), and blunted the angiotensin II-dependent changes in the levels and/or activation of AMP38 activated protein kinase (AMPK), ERK and myosin light chain. In contrast, myography showed comparable vascular reactivity in thoracic aortas and mesenteric arteries isolated from WT or CGNL1-KO mice. Together, these results suggest the KO of CGNL1 attenuates hypertension by uncoupling angiotensin II signaling in kidney tubule cells, indicating a novel pathway of regulation of signaling by a junctional protein. Hypertension Angiotensin Ion transport Kidney Paracingulin Dewey 612 Dewey 616.07 Dewey 616 Dewey 617 Dewey 570 Swiss National Science Foundation The functions of cingulin, paracingulin and PLEKHA7 at epithelial junctions 135730 CH Projects Swiss National Science Foundation Signaling at epithelial apical junctions 152899 CH Projects Swiss National Science Foundation Signalling by zonular junctional proteins in epithelia and endothelia 172809 CH Projects Swiss National Science Foundation Cytoplasmic proteins of apical junctions: from molecular and cellular mechanisms to physiopathology of disease 200681 CH Projects Swiss National Science Foundation Modulation of kidney tubule paracellular permeability in health and disease 207441 CH Projects Swiss National Science Foundation A multifaceted role for Panx1 in atherosclerosis 182573 CH Projects Swiss National Science Foundation The role of pannexin1 in cardiac ischemia/reperfusion injury 212291 CH Projects 137 Département de pathologie et immunologie 21F 134 Département de physiologie cellulaire et métabolisme 21C 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 56 Département de médecine 221 7daed2ee-1311-4824-9df9-2e51260a966a Département de biologie moléculaire et cellulaire 16484 false 397 Connexines et pathologies cardiovasculaires 665 897 Insuffisance rénale chronique 941 20 Laboratoire de physiologie et pathophysiologie des cellules rénales 29 1441 Groupe Citi https://yareta.unige.ch/archives/4f16213c-fcd9-4593-af9a-422210a650bd American journal of physiology. Renal physiology 2e26bba6-a7a7-4748-b3fd-2ef0fff50fb2 Article (Accepted version) Public rouaud-et-al-2025-the-knock-out-of-.pdf 4823439 application/pdf Restricted 2026-04-10 87a33cf93a48943756f7234a3d069b80a9df7de7f19d1a360e6db0a32a17654a b5dbcd89-de6b-49b0-854a-6e6d788f1956 Supplemental data Public Supplemental_Figures_Legends_Rouaud.pdf 8175786 application/pdf Restricted 2026-04-10 b07c347ec79b50be8f415c99b04d434cf3d74a4c916cbb9271e3bca871b66caf openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences Faculté de médecine / Section de médecine clinique / Département de médecine Faculté des sciences / Section de biologie / Département de biologie moléculaire et cellulaire

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Maillard, Marc Aimé Charles