Aldosterone Activates NF-κB in the Collecting Duct

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

Neutrophil Gelatinase-Associated Lipocalin Is a Novel Mineralocorticoid Target in the Cardiovascular System

“…34 Conversely, activation of NF-B by Aldo has been reported in renal collecting duct cells; however, this may not be a direct effect but rather an adaptative phenomenon to limit excessive Aldo signaling. 35 In cardiac cells, balance between MR and NF-B may regulate NGAL expression; this balance may be different after short-term and long-term situations and even more in a pathological context. Further experiments are needed to test such hypotheses, to understand how and why NGAL levels vary.…”

Aldosterone as a renal growth factor

“…The NF B transcriptional pathway is also activated in response to aldosterone in renal principal collecting duct cells however this was mediated by SGK activity rather than the stimulation of MAP kinases. The transcription of pro-inflammatory cytokine genes such as IL-1 and IL-6 are up-regulated by NF B [26]. The activation of NF Bdependent transcription in this experimental system was MR-dependent and was antagonized by concurrent activation of the glucocorticoid receptor.…”

Untitled

“…Aldosterone promotes inflammation via the mineralocorticoid receptor (MR) and can increase nicotinamide dinucleotide phosphate oxidase levels with secondary oxidative stress in tissues expressing MR [7]. Other inflammatory markers also increase with formation of reactive oxygen species and induction of proinflammatory genes [8]. Also, aldosterone can induce inflammation in cells lacking MR by the enzyme 11-β-hydroxysteroid dehydrogenase type 2 (11βHSD-2) [9].…”