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Arthritis Research and Therapy

, 10:R5

First Online: 15 January 2008Received: 22 September 2007Revised: 11 December 2007Accepted: 15 January 2008


BackgroundThe 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.

MethodsFemale 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.

ResultsTreatment 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.

ConclusionAldosterone 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.

AbbreviationsautoAb= autoantibody

BlyS= B lymphocyte stimulator

dsDNA= double-stranded DNA

GEO= Gene Expression Omnibus

IC= immune complex

IFN= interferon

PCR= polymerase chain reaction

SLE= systemic lupus erythematosus

ssDNA= single-stranded DNA

TRAIL= tumor necrosis factor related apoptosis-inducing ligand

TWEAK= tumor necrosis factor-like weak inducer of apoptosis.

Electronic supplementary materialThe online version of this article doi:10.1186-ar2353 contains supplementary material, which is available to authorized users.

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Autor: Seetha U Monrad - Paul D Killen - Marc R Anderson - Amanda Bradke - Mariana J Kaplan


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