Aldosterone activates NF-kappaB in the collecting duct.
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.
Leroy
Valérie
V
Foundation for Medical Research, University of Geneva, 64 Avenue de la Roseraie, CH-1211, Geneva 4, Switzerland.
De Seigneux
Sophie
S
Agassiz
Victor
V
Hasler
Udo
U
Rafestin-Oblin
Marie-Edith
ME
Vinciguerra
Manlio
M
Martin
Pierre-Yves
PY
Féraille
Eric
E
D021581:Active Transport, Cell Nucleus; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D051550:I-kappa B Kinase / Q000502:physiology; D020672:I-kappa B Proteins / Q000502:physiology; D017874:Immediate-Early Proteins / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D048049:Extracellular Signal-Regulated MAP Kinases; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C000606206:Nfkbia protein, rat; C498145:Rela protein, rat