Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury

Abstract

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.

Therapeutic targeting of neutrophil exocytosis

“…16,91,[146][147][148][149][150] Inhibition of neutrophil recruitment reduces organ injury in many animal models. [151][152][153][154][155][156][157][158] Data suggest that release of granule cargo and ROS generation mediate neutrophil-dependent organ damage. 154,159,160 A role for ROS is supported by finding oxidant-modified proteins in organs damaged by ischemia-reperfusion injury.…”

Role of Immune Cells in Acute Kidney Injury and Repair

“…However, discordant results led to questioning of the role of neutrophils during early AKI pathogenesis [2]. Recent studies, however, have shown that blocking neutrophil infiltration by inhibition of vascular adhesion protein-1 or leukotriene B4-leukotriene B4 receptor axis had protective effect against ischemia-reperfusion injury (IRI) and cisplatin-induced AKI, respectively [3,4]. …”

Epigenetic Changes in the Acute Kidney Injury-to-Chronic Kidney Disease Transition

“…VAP-1 is expressed predominantly in pericytes, which release enzymatically active VAP-1. Inhibition of VAP-1 decreased neutrophil infiltration and ameliorated renal ischemia-reperfusion injury in rats [6]. We also found that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel regulator of HIF-1, a master regulator of defensive mechanisms against hypoxia.…”