Polymorphonuclear leukocytes increase glomerular albumin permeability via hypohalous acid

Abstract

Acute glomerulonephritis is characterized by the presence of neutrophils within glomeruli and the generation of reactive oxygen species (ROS) by activated polymorphonuclear leukocytes (PMNs). Hydrogen peroxide (H2O2) and other ROS including hypohalous acids have been implicated in PMN mediated injury. To determine the role of specific ROS in PMN mediated glomerular injury, isolated rat glomeruli were incubated for 30 minutes at 37°C with H2O2, with H2O2 and myeloperoxidase, or with activated PMNs. Scavengers of ROS were included in some experiments. PMNs were harvested from rat peritoneal cavity and activated with phorbol myristate acetate (PMA). Glomerular albumin permeability (P(albumin)) was calculated from the volume response to an oncotic gradient. P(albumin) of glomeruli incubated with H2O2 (10-3 or 10-1 M) was not increased, while P(albumin) after incubation with H2O2 and MPO was markedly increased (0.94 ± 0.004). P,,,,,,, after incubation with PMA, or with non-activated PMNs was not different from that of control glomeruli. P(albumin) of the glomeruli incubated with activated PMNs increased (0.85 ± 0.01, P < 0.001). This increase in P(albumin) was inhibited by superoxide dismutase, catalase, or taurine (P(albumin) = 0.035 ± 0.06, -0.39 ± 0.10, 0.028 ± 0.06, respectively) and ameliorated by sodium azide (P(albumin) = 0.21 ± 0.03). In contrast, dimethyl sulfoxide did not prevent the increase in P(albumin) (P(albumin) = 0.92 ± 0.01). Our results show that the hypohalous acid derived from that of H2O2-MPO-halide system is capable of increasing P(albumin) We conclude that hypohalous acid may be the primary mediator of the immediate increase in glomerular protein permeability induced by PMNs.