Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury.
Vascular adhesion protein-1 (VAP-1) is a unique molecule since it acts as an adhesion molecule as well as an ectoenzyme catalyzing oxidative deamination of primary amines and generates hydrogen peroxide in the extracellular space. While VAP-1 is implicated in various inflammatory diseases, its role in acute kidney injury is less characterized. Here we studied VAP-1 expression in the kidney and the effect of its inhibition in a rat model of renal ischemia/reperfusion injury. VAP-1 was predominantly expressed in pericytes, which released enzymatically active enzyme. In vivo, a specific VAP-1 inhibitor, RTU-1096, significantly ameliorated rat renal ischemia/reperfusion injury and decreased neutrophil infiltration measured 12 hours after injury without altering macrophage or T lymphocyte populations. The protective effect of VAP-1 inhibition was lost in neutrophil-depleted rats, suggesting its inhibition ameliorated renal ischemia/reperfusion injury by suppressing neutrophil infiltration. To investigate whether hydrogen peroxide generated by VAP-1 enzyme reaction enhances neutrophil infiltration, we conducted an under-agarose migration assay with purified human neutrophils. Recombinant human VAP-1 significantly induced neutrophil migration, which was almost completely inhibited by RTU-1096 or catalase. Thus, VAP-1 plays a critical role in the pathophysiology of renal ischemia/reperfusion injury by enhancement of neutrophil infiltration generating a local hydrogen peroxide gradient. Hence, VAP-1 inhibition may be a novel therapy in ischemic acute kidney injury.
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Shinji
S
Tanaka
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Tetsuhiro
T
Tanaka
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Takahisa
T
Kawakami
Division of Nephrology, Tokyo Teishin Hospital, Tokyo, Japan.
Hideki
H
Takano
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Mai
M
Sugahara
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Hisako
H
Saito
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Yoshiki
Y
Higashijima
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Junna
J
Yamaguchi
Division of Chronic Kidney Disease Pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Reiko
R
Inagi
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan. Electronic address: mnangaku-tky@umin.ac.jp.
Masaomi
M
Nangaku
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D013997:Time Factors
D015815:Cell Adhesion Molecules; D006861:Hydrogen Peroxide; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse; C510433:vascular adhesion protein-1, rat
acute kidney injury; inflammation; ischemia reperfusion