1. Aldosterone Activates NF-κB in the Collecting Duct
- Author
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Sophie de Seigneux, Manlio Vinciguerra, Eric Féraille, Valérie Leroy, Marie-Edith Rafestin-Oblin, Udo Hasler, Pierre-Yves Martin, and Victor Agassiz
- Subjects
Male ,Transcription Factor RelA/metabolism ,Extracellular Signal-Regulated MAP Kinases/physiology ,p38 Mitogen-Activated Protein Kinases ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Transactivation ,Mineralocorticoid receptor ,Glucocorticoid receptor ,NF-KappaB Inhibitor alpha ,Protein-Serine-Threonine Kinases/physiology ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Aldosterone ,Cells, Cultured ,ddc:616 ,NF-kappa B ,General Medicine ,I-kappa B Kinase ,Immediate-Early Proteins/physiology ,Nephrology ,I-kappa B Proteins ,Signal transduction ,I-kappa B Kinase/physiology ,Kidney Tubules, Collecting/metabolism ,medicine.medical_specialty ,medicine.drug_class ,Active Transport, Cell Nucleus ,Aldosterone/pharmacology ,Protein Serine-Threonine Kinases ,Biology ,Immediate-Early Proteins ,Internal medicine ,Sodium Chloride, Dietary/administration & dosage ,medicine ,Animals ,Kidney Tubules, Collecting ,Sodium Chloride, Dietary ,ddc:612 ,Transcription Factor RelA ,Rats ,Receptors, Mineralocorticoid ,Basic Research ,Endocrinology ,chemistry ,Mineralocorticoid ,Receptors, Mineralocorticoid/drug effects/physiology ,NF-kappa B/metabolism ,I-kappa B Proteins/physiology ,SGK1 ,P38 Mitogen-Activated Protein Kinases/physiology ,Homeostasis - Abstract
Besides its classical effects on salt homeostasis in renal epithelial cells, aldosterone promotes inflammation and fibrosis and modulates cell proliferation. The proinflammatory transcription factor NF-kappaB has been implicated in cell proliferation, apoptosis, and regulation of transepithelial sodium transport. The effect of aldosterone on the NF-kappaB pathway in principal cells of the cortical collecting duct, a major physiologic target of aldosterone, is unknown. Here, in both cultured cells and freshly isolated rat cortical collecting duct, aldosterone activated the canonical NF-kappaB signaling pathway, leading to increased expression of several NF-kappaB-targeted genes (IkappaBalpha, plasminogen activator inhibitor 1, monocyte chemoattractant protein 1, IL-1beta, and IL-6). Small interfering RNA-mediated knockdown of the serum and glucocorticoid-inducible kinase SGK1, a gene induced early in the response to aldosterone, but not pharmacologic inhibition of extracellular signal-regulated kinase and p38 kinase, attenuated aldosterone-induced NF-kappaB activation. Pharmacologic antagonism or knockdown of the mineralocorticoid receptor prevented aldosterone-induced NF-kappaB activity. In addition, activation of the glucocorticoid receptor inhibited the transactivation of NF-kappaB by aldosterone. In agreement with these in vitro findings, spironolactone prevented NF-kappaB-induced transcriptional activation observed in cortical collecting ducts of salt-restricted rats. In summary, aldosterone activates the canonical NF-kappaB pathway in principal cells of the cortical collecting duct by activating the mineralocorticoid receptor and by inducing SGK1.
- Published
- 2009