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Epithelial Sodium Channel Is a Key Mediator of Growth Hormone-Induced Sodium Retention in Acromegaly

Institut National de la Santé et de la Recherche Médicale (INSERM) (P.K., S.V,. G.M., P.C., M.L.), Unité (U) 693, Le Kremlin Bicêtre F-94276, France; Université Paris-Sud 11 (P.K., S.V., G.M., P.C., M.L.), Faculté de Médecine Paris-Sud, Unité Mixte de Recherche (UMR)-S693, Le Kremlin Bicêtre F-94276, France; Assistance Publique-Hôpitaux de Paris (A.B.), Hôpital Européen Georges Pompidou, Centre d’Investigation Clinique, Paris F-75908, France; Assistance Publique-Hôpitaux de Paris (G.M.), Hôpital de Bicêtre, Service de Pharmacogénétique, Biochimie Moléculaire et Hormonologie, Le Kremlin Bicêtre F-94275, France; INSERM (P.Z.), U549, Centre Broca, Paris F-75014, France; Université Pierre et Marie Curie (M.I.-T., A.D.), Université Paris 06, UMR 7134 Paris F-75006, France; Centre National de la Recherche Scientifique (M.I.-T., A.D.), UMR 7134, Paris F-75006, France; and Assistance Publique-Hôpitaux de Paris (P.C., M.L.), Hôpital de Bicêtre, Service d’Endocrinologie et Maladies de la Reproduction, Le Kremlin Bicêtre F-94275, France

Address all correspondence and requests for reprints to: Marc Lombès, M.D., Ph.D., Institut National de la Santé et de la Recherche Médicale Unité 693, Faculté de Médecine Paris-Sud, 63, rue Gabriel Péri, 94276 Le Kremlin Bicêtre Cedex France. E-mail: marc.lombes{at}u-psud.fr.

Acromegalic patients present with volume expansion and arterial hypertension, but the renal sites and molecular mechanisms of direct antinatriuretic action of GH remain unclear. Here, we show that acromegalic GC rats, which are chronically exposed to very high levels of GH, exhibited a decrease of furosemide-induced natriuresis and an increase of amiloride-stimulated natriuresis compared with controls. Enhanced Na⁺,K⁺-ATPase activity and altered proteolytic maturation of epithelial sodium channel (ENaC) subunits in the cortical collecting ducts (CCDs) of GC rats provided additional evidence for an increased sodium reabsorption in the late distal nephron under chronic GH excess. In vitro experiments on KC3AC1 cells, a murine CCD cell model, revealed the expression of functional GH receptors and IGF-I receptors coupled to activation of Janus kinase 2/signal transducer and activator of transcription 5, ERK, and AKT signaling pathways. That GH directly controls sodium reabsorption in CCD cells is supported by: 1) stimulation of transepithelial sodium transport inhibited by GH receptor antagonist pegvisomant; 2) induction of -ENaC mRNA expression; and 3) identification of signal transducer and activator of transcription 5 binding to a response element located in the -ENaC promoter, indicative of the transcriptional regulation of -ENaC by GH. Our findings provide the first evidence that GH, in concert with IGF-I, stimulates ENaC-mediated sodium transport in the late distal nephron, accounting for the pathogenesis of sodium retention in acromegaly.