Dataset Information

Bradykinin 1 receptor blockade subdues systemic autoimmunity, renal inflammation, and blood pressure in murine lupus nephritis.

ABSTRACT:

Objective

The goal of this study was to explore the role of bradykinins and bradykinin 1 receptor (B1R) in murine lupus nephritis.

Methods

C57BL/6 and MRL/lpr mice were compared for renal expression of B1R and B2R by western blot and immunohistochemistry. MRL/lpr lupus-prone mice were administered the B1R antagonist, SSR240612 for 12?weeks, and monitored for blood pressure, proteinuria, renal function, and serum autoantibodies.

Results

Renal B1R:B2R ratios were significantly upregulated in MRL/lpr mice compared with B6 controls. B1R blockade ameliorated renal pathology lesions, proteinuria, and blood pressure, accompanied by lower serum IgG and anti-dsDNA autoantibody levels, reduced splenic marginal zone B cells and CD4⁺ T cells, and renal infiltrating CD4⁺ T cells, macrophages, and neutrophils. Both urine and renal CCL2 and CCL5 chemokines were also decreased in the B1R blocked MRL/lpr mice.

Conclusion

Bradykinin receptor B1R blockade ameliorates both systemic immunity and renal inflammation possibly by inhibiting multiple chemokines and renal immune cell infiltration. B1R blockade may be particularly attractive in subjects with concomitant lupus nephritis and hypertension.

SUBMITTER: Qin L

PROVIDER: S-EPMC6325757 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Bradykinin 1 receptor blockade subdues systemic autoimmunity, renal inflammation, and blood pressure in murine lupus nephritis.

Qin Ling L Du Yong Y Ding Huihua H Haque Anam A Hicks John J Pedroza Claudia C Mohan Chandra C

Arthritis research & therapy 20190108 1

<h4>Objective</h4>The goal of this study was to explore the role of bradykinins and bradykinin 1 receptor (B1R) in murine lupus nephritis.<h4>Methods</h4>C57BL/6 and MRL/lpr mice were compared for renal expression of B1R and B2R by western blot and immunohistochemistry. MRL/lpr lupus-prone mice were administered the B1R antagonist, SSR240612 for 12 weeks, and monitored for blood pressure, proteinuria, renal function, and serum autoantibodies.<h4>Results</h4>Renal B1R:B2R ratios were significantl ...[more]

PMID: 30621761

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Project description:BackgroundThe purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB x 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 microg/ml versus 1,036 microg/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 microg/ml versus 614 microg/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-gamma, 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.

Dataset Information

Bradykinin 1 receptor blockade subdues systemic autoimmunity, renal inflammation, and blood pressure in murine lupus nephritis.

Objective

Methods

Results

Conclusion

Publications

Bradykinin 1 receptor blockade subdues systemic autoimmunity, renal inflammation, and blood pressure in murine lupus nephritis.

Similar Datasets

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