Aldosterone-induced kidney injury is mediated by NFκB activation.
Summary of "Aldosterone-induced kidney injury is mediated by NFκB activation."
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.
Affiliation
Department of Internal Medicine, International University of Health and Welfare, Mita Hospital, 1-4-3 Mita, Minato-ku, Tokyo, 108-8329, Japan.
Journal Details
This article was published in the following journal.
Name: Clinical and experimental nephrology
ISSN: 1437-7799
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21072674
- DOI: http://dx.doi.org/10.1007/s10157-010-0373-1
Medical and Biotech [MESH] Definitions
Signal Transduction
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activa
Hypoaldosteronism
A congenital or acquired condition of insufficient production of ALDOSTERONE by the ADRENAL CORTEX leading to diminished aldosterone-mediated synthesis of Na(+)-K(+)-EXCHANGING ATPASE in renal tubular cells. Clinical symptoms include HYPERKALEMIA, sodium-wasting, HYPOTENSION, and sometimes metabolic ACIDOSIS.
Acute Kidney Injury
Abrupt reduction in kidney function defined as an absolute increase in serum CREATININE of more than or equal to 0.3. mg/dl, a percentage increase in serum creatinine of more than or equal to 50%, or a reduction in urine output. Acute kidney injury encompasses the entire spectrum of the syndrome including acute kidney failure; ACUTE KIDNEY TUBULAR NECROSIS; and other less severe conditions.
Receptors, Aldosterone
Cytoplasmic proteins that specifically bind aldosterone and mediate its cellular effects. The aldosterone-bound receptor acts in the nucleus to regulate the transcription of specific segments of DNA.
Aldosterone Antagonists
Compounds which inhibit or antagonize the biosynthesis or actions of aldosterone.
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