Aldosterone Activates NF- B in the Collecting Duct

Foundation for Medical Research, University of Geneva, 64 Avenue de la Roseraie, CH-1211, Geneva 4, Switzerland.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 12/2008; 20(1):131-44. DOI: 10.1681/ASN.2008020232
Source: PubMed


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.

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Available from: Manlio Vinciguerra
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    • "Previous findings have shown that STAT3 plays an essential role in glucose homeostasis by regulating the expression of gluconeogenic genes in the liver [92]; therefore, it likely plays the same role in glucose homeostasis in the kidney [57]. NFKB1, which interacts with RELA to form the NF-kB complex, is essential for proper functioning of the immune system and modulates transepithelial sodium transport in the kidney [93], [94]. APP and APOE are involved in the transport of ions (e.g., sodium) and lipids, respectively. "
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    • "A large body of animal and clinical studies also reported that spironolactone has potent anti-inflammatory effects in multiple organs and systems via mineralocorticoid receptor or non-mineralocorticoid receptor mechanisms. For example, first, in principal cells of the cortical collecting duct, spironolactone attenuated aldosterone-induced inflammatory cytokines production such as IL-1β and IL-6 via mineralocorticoid receptor-dependent pathway [43], second, in human mononuclear cells, spironolactone inhibited the activation of NF-κβ and the expression of several NF-κβ-targeted genes via non-mineralocorticoid receptor mechanisms [44], [45], third, in rheumatoid arthritis patients, treatment with spironolactone improves both endothelial dysfunction and inflammatory disease activity [24], [27]. In our present study, we also found a robust anti-inflammatory effect of spironolactone. "
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    • "MR is known to be present in other kidney cells, including mesangial cells and renal fibroblasts, and to modulate their functions via profibrotic action or alteration of cell cycle regulators [30]. In addition, aldosterone activates NF-κB in principal cells of the cortical collecting duct through mechanisms that involve SGK1 [31]. NF-κB regulates inflammation and transepithelial sodium transport, so this observation indicates a convergence of sodium reabsorption and inflammatory stimulation in the collecting duct. "
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