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Clin Exp Nephrol. 2011 Feb;15(1):41-9. doi: 10.1007/s10157-010-0373-1. Epub 2010 Nov 12.

Aldosterone-induced kidney injury is mediated by NFκB activation.

Author information

1
Department of Internal Medicine, International University of Health and Welfare, Mita Hospital, 1-4-3 Mita, Minato-ku, Tokyo 108-8329, Japan.

Abstract

BACKGROUND:

Aldosterone induces inflammation and fibrosis in the kidney, while nuclear factor κB (NFκB) plays key roles in inflammation mediated by various cytokines. Here, we determined the roles of NFκB activation in aldosterone-induced kidney injury.

METHODS:

We used unilaterally nephrectomized rats with or without continuous aldosterone infusion and 0.9% saline as drinking water for 3 weeks. IMD-1041, an IKKβ inhibitor, and spironolactone were orally administered to inhibit NFκB and mineralocorticoid receptor, respectively.

RESULTS:

The aldosterone-infused rats exhibited severe kidney injury, hypertension, and increased expression of pro-inflammatory and fibrotic proteins, osteopontin, fibrinogen, collagen type I, and PAI-1. Western blotting confirmed NFκB activation by aldosterone by the increased amount of p65 in the nuclear fraction of the kidney, and oral IMD-1041 prevented the kidney injury and lessened the increase in pro-inflammatory and fibrotic proteins without significant changes in blood pressures. In addition, changes in angiotensin-converting enzyme 2 (ACE2), which has been found to act as a protective factor in various kidney injury models, were examined. Immunofluorescence studies revealed the presence of ACE2 in the brush-border membrane of the proximal convoluted tubules and markedly blunted ACE2 staining in aldosterone-infused rats. The decrease in amount of ACE2 protein was confirmed by Western blotting, and IMD-1041 also prevented the decrease in ACE2. The administration of spironolactone also abolished the effects of aldosterone.

CONCLUSION:

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.

PMID:
21072674
DOI:
10.1007/s10157-010-0373-1
[Indexed for MEDLINE]

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