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

Ling Qin,Chandra Mohan,Anam Haque,John Hicks,Huihua Ding,Claudia Pedroza,Yong Du

doi:10.1186/s13075-018-1774-x

Abstract

ObjectiveThe goal of this study was to explore the role of bradykinins and bradykinin 1 receptor (B1R) in murine lupus nephritis.MethodsC57BL/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.ResultsRenal 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.ConclusionBradykinin 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.

Highlights

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder characterized by the production of autoantibodies, multiple organ involvement, and diverse clinical manifestations
Renal expression of bradykinin 1 receptor (B1R) and B2R in MRL/lpr mice assayed using two complementary approaches To explore the renal expression of bradykinin receptors B1R and B2R in MRL/lpr mice, total renal protein was extracted and examined by western blot
Renal B1R expression was increased in MRL/lpr mice compared with C57BL/6 J mice (Fig. 1a, c), whereas renal B2R expression was decreased in MRL/lpr mice compared with C57BL/6 J mice (Fig. 1b, d)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder characterized by the production of autoantibodies, multiple organ involvement, and diverse clinical manifestations. It has been reported that B1R is involved in inflammation, pain, and fibrosis induced by inflammatory mediators This receptor-mediated pathway has been implicated in inflammatory bowel disease, vasculitis, experimentally induced nephritis, and acute gout [1,2,3,4]. In resonance with these reports, it has been shown that B1R antagonism or ablation plays a protective role in nephrotoxic serum-induced glomerulonephritis [5], lipopolysaccharide (LPS)-mediated acute renal inflammation [6], and experimental obstructive nephropathy [7].

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