Aldosterone Activates NF-κB in the Collecting Duct

• Published in: Journal of the American Society of Nephrology Vol. 20; no. 1; pp. 131 - 144
• Main Authors: LEROY, Valérie, DE SEIGNEUX, Sophie, AGASSIZ, Victor, HASLER, Udo, RAFESTIN-OBLIN, Marie-Edith, VINCIGUERRA, Manlio, MARTIN, Pierre-Yves, FERAILLE, Eric
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 2009
• Subjects: Basic Research; Biological and medical sciences; Medical sciences; Nephrology. Urinary tract diseases; Nephrology; Urinary system; Steroid hormone; Mineralocorticoid; Adrenal hormone; Collecting duct; Transcription factor NFκB; Aldosterone; Kidney; Urology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2008020232

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-κB has been implicated in cell proliferation, apoptosis, and regulation of transepithelial sodium transport. The effect of aldosterone on the NF-κB 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-κB signaling pathway, leading to increased expression of several NF-κB–targeted genes (IκBα, plasminogen activator inhibitor 1, monocyte chemoattractant protein 1, IL-1β, 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-κB activation. Pharmacologic antagonism or knockdown of the mineralocorticoid receptor prevented aldosterone-induced NF-κB activity. In addition, activation of the glucocorticoid receptor inhibited the transactivation of NF-κB by aldosterone. In agreement with these in vitro findings, spironolactone prevented NF-κB–induced transcriptional activation observed in cortical collecting ducts of salt-restricted rats. In summary, aldosterone activates the canonical NF-κB pathway in principal cells of the cortical collecting duct by activating the mineralocorticoid receptor and by inducing SGK1.