Aldosterone-induced kidney injury is mediated by NFκB activation

Fukuda, Seiichi; Horimai, Chihiro; Harada, Kaori; Wakamatsu, Toshifumi; Fukasawa, Hiroshi; Muto, Shoshi; Itai, Akiko; Hayashi, Matsuhiko

doi:10.1007/s10157-010-0373-1

Cited by 33 publications

(29 citation statements)

References 27 publications

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“…[24][25][26][27][28] Importantly, the aldosterone-induced damage to the heart and kidneys is largely independent of the systemic effects on blood pressure. 10,29 Inflammation and fibrosis seem to play central roles in the pathophysiology of both cardiac and renal aldosteroneinduced injury.…”

Section: February 2015mentioning

confidence: 99%

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

2015

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Section: February 2015mentioning

confidence: 99%

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

2015

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“…NFB and AP-1 are activated in hypertensive rats given ALD and high salt diets (22,23), but blood pressure, shear forces, and secondary mediators, such as endothelin-1 and angiotensin, may play prominent roles in these models. In addition, the frequent use of spironolactone in numerous studies to confirm MR pathway specificity is confounded by its protean and incompletely understood off target effects (24).…”

mentioning

confidence: 99%

Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling

Dougherty

Elinoff

Ferreyra

et al. 2016

Journal of Biological Chemistry

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Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes, such as NFB and AP-1, and trans-repress the transcription of cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. Although MR has been shown to weakly repress NFB, its role in modulating AP-1 has not been established. Here, the effects of GR and MR on NFB and AP-1 signaling were directly compared using a variety of ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both GR and MR repressed an NFB reporter without influencing p65 or p50 binding to DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and AP-1 family member-specific manner. Notably, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations that eliminated the ability of GR and MR to cis-activate a hormone response element-driven reporter variably affected the strength and polarity of these responses. Importantly, MR modulation of NFB and AP-1 signaling was consistent with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets in primary human cells. Steroid nuclear receptor trans-effects on inflammatory signaling are context-dependent and influenced by nuclear receptor conformation, DNA sequence, and the expression of heterologous binding partners. Aldosterone activation of AP-1 may contribute to its proinflammatory effects in the vasculature.

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“…57 In this study, unilateral nephrectomy and treatment with DOCA/salt induced renal organ damage, including inflammation, renal fibrosis, glomerular injury, and proteinuria as expected. 16,20,30,54 However, this was independent from endothelial MR deletion.…”

Section: Doca/salt-induced Kidney Injury Is Independent From Endothelmentioning

confidence: 92%

“…16,[20][21][22] There is some evidence that aldosteroneinduced end organ damage in the heart and the kidney is based on similar mechanisms, particularly on an inflammatory response mediated by MR activation. 12,23 Secretion of cytokines and the expression of adhesive molecules in endothelial cells are major regulators of immune cell attraction and activation within many tissues.…”

mentioning

confidence: 99%

Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

et al. 2016

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Abstract-Chronic kidney disease has a tremendously increasing prevalence and requires novel therapeutic approaches.Mineralocorticoid receptor (MR) antagonists have proven highly beneficial in the therapy of cardiac disease. The cellular and molecular events leading to cardiac inflammation and remodeling are proposed to be similar to those mediating renal injury. Thus, this study was designed to evaluate and directly compare the effect of MR deletion in endothelial cells on cardiac and renal injury in a model of deoxycorticosterone acetate-induced hypertension. Endothelial MR deletion ameliorated deoxycorticosterone acetate/salt-induced cardiac remodeling. This was associated with a reduced expression of the vascular cell adhesion molecule Vcam1 in MR-deficient cardiac endothelial cells. Ambulatory blood pressure telemetry revealed that the protective effect of MR deletion was independent from blood pressure. Similar to the heart, deoxycorticosterone acetate/salt-induced severe renal injury, including inflammation, fibrosis, glomerular injury, and proteinuria. However, no differences in renal injury were observed between genotypes. In conclusion, MR deletion from endothelial cells ameliorated deoxycorticosterone acetate/salt-induced cardiac inflammation and remodeling independently from alterations in blood pressure but it did not affect renal injury. These findings suggest that the anti-inflammatory mechanism mediating organ protection after endothelial cell MR deletion is specific for the heart versus the kidney.

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Aldosterone-induced kidney injury is mediated by NFκB activation

Abstract: Our results suggest that aldosterone induces kidney injury via activation of NFκB and mineralocorticoid receptor, and that decreased ACE2 expression may play an important role in aldosterone-induced kidney injury.

Cited by 33 publications

References 27 publications

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling

Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

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