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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2008

Open Access 01-02-2008 | Research article

The role of aldosterone blockade in murine lupus nephritis

Authors: Seetha U Monrad, Paul D Killen, Marc R Anderson, Amanda Bradke, Mariana J Kaplan

Published in: Arthritis Research & Therapy | Issue 1/2008

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Abstract

Background

The purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB × NZW) F1 murine lupus model.

Methods

Female NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria, renal function, and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points. Targeted microarray analysis was performed on renal tissue, with subsequent real-time PCR analysis of several differentially expressed genes.

Results

Treatment with spironolactone was well tolerated by the mice throughout the course of their disease progression, with no significant differences in azotemia or serum potassium levels between vehicle-treated and spironolactone-treated animals. By 36 weeks of age, fewer spironolactone-treated mice developed nephrotic range proteinuria as compared with the control mice (control 70.8%, 25 mg/kg spironolactone 51.3%, and 50 mg/kg spironolactone 48.6%). Compared with control mice, mice treated with 25 mg/kg spironolactone had significantly lower serum anti-single-stranded DNA levels (2,042 μg/ml versus 1,036 μg/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 μg/ml versus 614 μg/ml; P = 0.05). Spironolactone-treated mice exhibited decreased histopathologic evidence of inflammation and tissue damage, as compared with control mice. Additionally, spironolactone treatment resulted in decreased expression in the kidney of several inflammatory and proapoptotic genes, including those encoding interferon-γ, B lymphocyte stimulator (BlyS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), tumor necrosis factor related weak inducer of apoptosis (TWEAK), and Fas ligand.

Conclusion

Aldosterone receptor blockade is safe and well tolerated in progressive murine lupus nephritis, and it results in decreased levels of clinical proteinuria, lower serum levels of autoantibodies, and decreased kidney damage. It appears to modulate inflammatory changes during the progression of glomerulonephritis and may also have a previously undescribed role in attenuating apoptosis.
Appendix
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Metadata
Title
The role of aldosterone blockade in murine lupus nephritis
Authors
Seetha U Monrad
Paul D Killen
Marc R Anderson
Amanda Bradke
Mariana J Kaplan
Publication date
01-02-2008
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2008
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar2353

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