Article

Aldosterone activates NF-kappaB 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: 8.99). 12/2008; 20(1):131-44. DOI: 10.1681/ASN.2008020232
Source: PubMed

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.

0 Bookmarks
 · 
113 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Excessive levels of the glycolysis metabolite methylglyoxal (MG) elicit enhanced expression of adhesion molecules which foster leukocyte-endothelial cell interactions. The signaling mechanisms involved remain elusive. To address this, we investigated the signal transduction of leukocyte- and endothelial-expressed phosphoinositide 3-kinase (PI3K) effector kinases glycogen synthase kinase 3 (GSK3) and serum- and glucocorticoid-inducible kinase 1 (SGK1) in the regulation of MG-elicited leukocyte recruitment. Using intravital microscopy of mouse cremasteric microvasculature, we demonstrate that GSK3 inhibitors lithium and SB216763 mitigate MG-elicited leukocyte recruitment and microvascular hyperpermeability. In SVEC4-10EE2 endothelial cells, but not in neutrophils, MG transiently activates GSK3 by reducing inhibitory phospho-GSK3α/β (Ser21/9) which parallels decrease of phospho-Akt at early time points (˂30min). At later time points (˃1h), MG induces GSK3 deactivation which is dissipated by siRNA silencing of SGK. MG treatment potentiates endothelial SGK1 mRNA, total SGK1, phospho-SGK1 and phospho-NDRG1. The SGK1 inhibitor GSK650394 attenuates MG-elicited leukocyte recruitment. Pharmacological inhibition or silencing endothelial GSK3 or SGK attenuates MG-triggered nuclear factor (NF)-κB activity. Furthermore, silencing SGK blunts MG-triggered redox-sensitive phosphorylation of endothelial transcription factor CREB. Inhibition of SGK1 or GSK3 mitigates the expression of endothelial adhesion molecules P- and E-selectins and ICAM-1. Moreover, SGK1-dependent CREB activation participates in MG-elicited ICAM-1 upregulation. We conclude that temporal activation of endothelial SGK1 and GSK3 is decisive in MG-elicited upregulation of transcription factors, adhesion molecule expression, and leukocyte-vascular endothelium interactions. This novel signaling pathway may link excessive MG levels in vivo to inflammation, thus, unravelling potential therapeutic targets.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 07/2014; · 4.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atherosclerosis is a chronic inflammatory disease in the vessel. As a representative inflammatory cytokine, C-reactive protein (CRP) participates in atherogenesis. Although hyperaldosteronism is known to evoke inflammatory response in several tissues and cell types, there is no direct evidence to demonstrate the proinflammatory effect of aldosterone on vascular smooth muscle cells (VSMCs) through CRP. In this study, we observed effect of aldosterone on CRP expression and the molecular mechanisms in rat VSMCs. The results showed that aldosterone induced CRP expression in VSMCs in vitro and in vivo. Mineralocorticoid receptor (MR) antagonist spironolactone abolished aldosterone-induced CRP expression. In addition, aldosterone stimulated generation of reactive oxygen species (ROS) and activated ERK1/2 phosphorylation, whereas spironolactone inhibited aldosterone-stimulated ROS generation and ERK1/2 phosphorylation. Antioxidant NAC decreased aldosterone-induced CRP expression and ERK1/2 phosphorylation. The further study confirmed that ERK1/2 inhibitor PD98059 and NF-κB inhibitor pyrrolidine dithiocarbamate both depressed aldosterone-induced CRP expression. These demonstrate that aldosterone is able to induce CRP expression via MR-ROS-ERK1/2-NF-κB signal pathway in VSMCs, which provides a new evidence for the proinflammatory and proatherosclerotic effects of aldosterone.
    Molecular and Cellular Endocrinology 09/2014; · 4.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Localized inflammation of lumbar dorsal root ganglia (DRG) may contribute to low back pain. Local injections of corticosteroids used for low back pain are sometimes ineffective. Many corticosteroids activate not only the target glucocorticoid receptor (GR) but also the mineralocorticoid receptor (MR), which may have proinflammatory effects countering the effects of GR activation. A low back pain model was implemented in rats (n = 6 to 10 per group) by locally inflaming the L5 DRG. Sensory neuron excitability and mechanical hypersensitivity of the hind paws were measured. Tested steroids were applied locally to the inflamed DRG or orally. The selective MR blocker eplerenone reduced pain behaviors when given orally starting at the time of surgery, or starting 7 days later. The highly GR-selective agonist fluticasone, applied locally to the inflamed DRG, was much more effective in reducing mechanical hypersensitivity. The MR/GR agonist 6-α methylprednisolone, commonly injected for low back pain, reduced mechanical hypersensitivity when applied locally to the DRG but was less effective than fluticasone. Its effectiveness was improved by combining it with local eplerenone. All tested steroids reduced hyperexcitability of myelinated sensory neurons (n = 71 to 220 cells per group) after inflammation, particularly abnormal spontaneous activity. This preclinical study indicates the MR may play an important role in low back pain involving inflammation. Some MR effects may occur at the level of the sensory neuron. It may be useful to consider the action of clinically used steroids at the MR as well as at the GR.
    Anesthesiology 04/2014; · 5.16 Impact Factor

Full-text

Download
76 Downloads
Available from
May 22, 2014