Epithelial Sodium Channel Is a Key Mediator of Growth Hormone-Induced Sodium Retention in Acromegaly
Open Access
- 3 April 2008
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 149 (7), 3294-3305
- https://doi.org/10.1210/en.2008-0143
Abstract
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 α-ENaC mRNA expression; and 3) identification of signal transducer and activator of transcription 5 binding to a response element located in the α-ENaC promoter, indicative of the transcriptional regulation of α-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.Keywords
This publication has 53 references indexed in Scilit:
- Acute Regulation of the Epithelial Na+ Channel by Phosphatidylinositide 3-OH Kinase Signaling in Native Collecting Duct Principal CellsJournal of the American Society of Nephrology, 2007
- Acute growth hormone administration induces antidiuretic and antinatriuretic effects and increases phosphorylation of NKCC2American Journal of Physiology-Renal Physiology, 2007
- The Mineralocorticoid Receptor: Insights into its Molecular and (Patho)Physiological BiologyNuclear Receptor Signaling, 2007
- Mechanisms of Mineralocorticoid ActionHypertension, 2005
- Expression and function of the human mineralocorticoid receptor: lessons from transgenic mouse modelsMolecular and Cellular Endocrinology, 2003
- Epithelial Sodium Channel and the Control of Sodium Balance: Interaction Between Genetic and Environmental FactorsAnnual Review of Physiology, 2002
- The role of STAT proteins in growth hormone signalingOncogene, 2000
- Activity of the Renin-Angiotensin-Aldosterone Axis is Dependent on the Occurrence of Edema in Growth Hormone(GH)-Deficient Adults Treated with GHJournal of Clinical Endocrinology & Metabolism, 1997
- In situ gene expression of growth hormone (GH) receptor and GH binding protein in adult male rat tissuesMolecular and Cellular Endocrinology, 1995
- BODY WATER AND SODIUM IN PATIENTS WITH ACROMEGALY 1JCI Insight, 1954