Kinin B1 Receptor Is Important in the Pathogenesis of Myeloperoxidase-Specific ANCA GN
Authors: Hu Peiqi , Su Hua , Xiao Hong , Gou Shen-Ju , Herrera Carolina A. , Alba Marco A. , Kakoki Masao , Falk Ronald J. , Jennette J. Charles 
Published: November 2019

Significance Statement
ANCAs specific for myeloperoxidase (MPO) and proteinase 3 are implicated in the pathogenesis of vasculitis and GN. Kinins play a major role in mediating acute inflammation, and kinin system activation occurs in patients with ANCA vasculitis. The authors investigated the role of bradykinin receptor 1 (B1R), which modulates leukocyte adhesion and migration, in the pathogenesis of MPO-ANCA GN in a murine model. By evaluating the effects of B1R genetic ablation and pharmacologic blockade on neutrophil activation, crescent formation and necrosis, glomerular leukocyte influx and transmigration, neutrophil adhesion molecule surface display, and relative importance of leukocyte B1R versus endothelial B1R, they determined that leukocyte B1R plays a critical role in murine MPO-ANCA GN pathogenesis by modulating neutrophil-endothelial interaction. Pharmacologic blockade of B1R might be a therapeutic option for ANCA GN and vasculitis.

Background
Myeloperoxidase-specific ANCA (MPO-ANCA) are implicated in the pathogenesis of vasculitis and GN. Kinins play a major role during acute inflammation by regulating vasodilatation and vascular permeability and by modulating adhesion and migration of leukocytes. Kinin system activation occurs in patients with ANCA vasculitis. Previous studies in animal models of GN and sclerosing kidney diseases have demonstrated protective effects of bradykinin receptor 1 (B1R) blockade via interference with myeloid cell trafficking.

Methods
To investigate the role of B1R in a murine model of MPO-ANCA GN, we evaluated effects of B1R genetic ablation and pharmacologic blockade. We used bone marrow chimeric mice to determine the role of B1R in bone marrow–derived cells (leukocytes) versus nonbone marrow–derived cells. We elucidated mechanisms of B1R effects using in vitro assays for MPO-ANCA–induced neutrophil activation, endothelial adherence, endothelial transmigration, and neutrophil adhesion molecule surface display.

Results
B1R deficiency or blockade prevented or markedly reduced ANCA-induced glomerular crescents, necrosis, and leukocyte influx in mice. B1R was not required for in vitro MPO-ANCA–induced neutrophil activation. Leukocyte B1R deficiency, but not endothelial B1R deficiency, decreased glomerular neutrophil infiltration induced by MPO-ANCA in vivo. B1R enhanced ANCA-induced neutrophil endothelial adhesion and transmigration in vitro. ANCA-activated neutrophils exhibited changes in Mac-1 and LFA-1, important regulators of neutrophil endothelial adhesion and transmigration: ANCA-activated neutrophils increased surface expression of Mac-1 and increased shedding of LFA-1, whereas B1R blockade reduced these effects.

Conclusions
The leukocyte B1R plays a critical role in the pathogenesis of MPO-ANCA–induced GN in a mouse model by modulating neutrophil–endothelial interaction. B1R blockade may have potential as a therapy for ANCA GN and vasculitis.