title: NF-kappaB inhibits sodium transport via down-regulation of SGK1 in renal collecting duct principal cells.
abstract: Tubulointerstitial inflammation is a common feature of renal diseases. We have investigated the relationship between inflammation and Na(+) transport in the collecting duct (CD) using the mCCD(cl1) and mpkCDD(cl4) principal cell models. Lipopolysaccharide (LPS) decreased basal and aldosterone-stimulated amiloride-sensitive transepithelial current in a time-dependent manner. This effect was associated with a decrease in serum and glucocorticoid-regulated kinase 1 (SGK1) mRNA and protein levels followed by a decrease in epithelial sodium channel (ENaC) alpha-subunit mRNA levels. The LPS-induced decrease in SGK1 expression was confirmed in isolated rat CD. This decreased expression of either SGK1 or the ENaC alpha-subunit was not due to enhanced degradation of mRNA. In contrast, LPS inhibited transcriptional activity of the SGK1 promoter measured by luciferase-reporter gene assay. The effect of LPS was not mediated by inhibition of mineralocorticoid or glucocorticoid receptor, because expression of both receptors was unchanged and blockade of either receptor by spironolactone or RU486, respectively, did not prevent the down-regulation of SGK1. The effect of LPS was mediated by the canonical NF-kappaB pathway, as overexpression of a constitutively active mutant, IKKbeta (inhibitor of nuclear factor kappaB kinase-beta) decreased SGK1 mRNA levels, and knockdown of p65 NF-kappaB subunit by small interfering RNA increased SGK1 mRNA levels. Chromatin immunoprecipitation showed that LPS increased p65 binding to two NF-kappaB sites along the SGK1 promoter. In conclusion, we show that activation of the NF-kappaB pathway down-regulates SGK1 expression, which might lead to decreased ENaC alpha-subunit expression, ultimately resulting in decreased Na(+) transport.
authors.affiliation: Service de Néphrologie, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: de Seigneux
authors.affiliation: Service de Néphrologie, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Leroy
authors.affiliation: Service de Néphrologie, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland.
authors.forename: Hafida
authors.initials: H
authors.lastname: Ghzili
authors.affiliation: Service de Néphrologie, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland.
authors.forename: Martine
authors.initials: M
authors.lastname: Rousselot
authors.affiliation: The Water and Salt Research Center, Institute of Anatomy, University of Aarhus, 8000 Aarhus, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Nielsen
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Rossier
authors.affiliation: Service de Néphrologie, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Martin
authors.affiliation: Service de Néphrologie, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland. Electronic address: Eric.Feraille@medecine.unige.ch.
authors.forename: Eric
authors.initials: E
authors.lastname: Féraille
mesh_terms: D000818:Animals; D001692:Biological Transport; D015536:Down-Regulation; D053503:Epithelial Sodium Channels / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000737:chemistry / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D012964:Sodium; D000099184:Serum-Glucocorticoid Regulated Kinases