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 hypothalous 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 degrees 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 (Palbumin) was calculated from the volume response to an oncotic gradient. Palbumin of glomeruli incubated with H2O2 (10(-3) or 10(-1) M) was not increased, while Palbumin after incubation with H2O2 and MPO was markedly increased (0.94 +/- 0.004). Palbumin after incubation with PMA, or with non-activated PMNs was not different from that of control glomeruli, Palbumin of the glomeruli incubated with activated PMNs increased (0.85 +/- 0.01, P< 0.001). This increase in Palbumin was inhibited by superoxide dismutase, catalase, or taurine (Palbumin = 0.035 +/- 0.06, -0.39 +/- 0.10, 0.028 +/- 0.06, respectively) and ameliorated by sodium azide (Palbumin = 0.21 +/- 0.03). In contrast, dimethyl sulfoxide did not prevent the increase in Palbumin (Palbumin = 0.92 +/- 0.01). Our results show that the hypohalous acid derived from that of H2O2-MPO-halide system is capable of increasing Palbumin. We conclude that hypohalous acid may be the primary mediator of the immediate increase in glomerular protein permeability induced by PMNs.

Endogenous Myeloperoxidase Promotes Neutrophil-Mediated Renal Injury, but Attenuates T Cell Immunity Inducing Crescentic Glomerulonephritis

“…This study demonstrated a functional pathogenic role of endogenous MPO in kidney damage during experimental neutrophilmediated GN. MPO is involved in the generation of a variety of injurious reactive intermediates, including HOCl, which has been shown to induce glomerular damage in vitro (39), and ROS, such as the hydroxyl radical and singlet oxygen (7). Previous studies showed that neutrophils contribute to glomerular injury by ROS production (40).…”

Direct Effects of Platelet-Activating Factor on Glomerular Capillary Permeability

“…(ii) a de crease in Ln after 60 min and (iii) an increase in Polbumin. The increase in Paibumin by PAF is less in magnitude than the in crease seen after treatment with superoxide, hydroxyl ion or during injury with antibody and complement [27][28][29], Mechanisms by which PAF might decrease GFR include increased renal vascular resistance, contraction of mesangi al cells and decreased filtering capillary area and/or de crease in Lp. The current studies document that PAF acts on the glomerulus in at least two ways to cause a decrease in GFR.…”

Circulating Permeability Factors in Idiopathic Nephrotic Syndrome and Focal Segmental Glomerulosclerosis

“…The assay reflects injury to the glomerular protein permeability barrier and is not specific to FSGS serum/ plasma. For example, agents as diverse as TNF␣, superoxide, or antibodies to protein tyrosine phosphatase receptor and ␤1 integrin increase P alb (42)(43)(44)(45)(46). Sera from some but not all patients with FSGS cause increased P alb in isolated glomeruli.…”