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

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.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1774-x) contains supplementary material, which is available to authorized users.

Upregulation of Proinflammatory Bradykinin Peptides in Systemic Lupus Erythematosus and Rheumatoid Arthritis

“…MRM is a nonscanning method that uses QQQ MS to measure low abundance analytes of interest in complex sample mixtures. Unlike other shotgun proteomic techniques, full mass spectra is not obtained in MRM (9,12). MRM can detect multiple peptides (multiplexing) in nanogram concentrations with high sensitivity and reproducibility.…”

“…Reduced glomerular and tubular lesions and improved renal function have been reported by Klein et al (8) in experimentally induced nephritis. We have recently shown that blocking the BK1R subdues lupus nephritis and blood pressure in MRL/ lpr lupus-prone mice (9).…”

Norcantharin ameliorates the development of murine lupus via limiting STAT3-mediated IL-17-producing cell accumulation

“…Previous study has proved that NCTD is able to protect renal functions via blocking renal inflammation and proteinuria [42], while the role of NCTD in SLE remains unknown. SLE is associated with lots of clinical and immunologic manifestations, in which LN is the most important predictor for morbidity and mortality [43]. Nephritis development in SLE patients are indicated by proteinuria, diffuse inflammation and decreased renal function for multiple pathogenic factors including aberrant cell apoptosis, autoantibody accumulation and immune complex deposition [44].…”

Heightened Crescentic Glomerulonephritis in Immune Challenged 129sv Mice Is TGF-β/Smad3 Dependent

“…Likewise, tubulo-interstitial injury was graded on a scale of 0–4 based on tubular atrophy, inflammatory infiltrates, interstitial fibrosis, and the severity of tubulo-interstitial nephritis (TIN) [ 15 , 16 ]. The inflammatory score was also evaluated by a renal pathologist in a blinded manner using a well-established histology scoring system based on H&E and PAS stained sections, as detailed in our earlier manuscripts [ 15 , 16 , 36 , 37 , 38 ].…”