Synthesis of hydroxyeicosatetraenoic acids and leukotrienes in rat nephrotoxic serum glomerulonephritis. Role of anti-glomerular basement membrane antibody dose, complement, and neutrophiles

Abstract

The basal and stimulated synthesis of immunoassayable 12- and 5-monohydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT) B4 and C4 was studied in glomeruli isolated from rats with nephrotoxic serum glomerulonephritis (NSGN) induced by low (30 micrograms/g body weight) or high (105 micrograms/g) doses of anti-rat glomerular basement membrane (GBM) immunoglobulin (Ig). In the early heterologous phase of the disease, low doses of anti-GBM Ig enhanced the basal synthesis of 12-HETE but not that of 5-HETE or LT. High anti-GBM Ig doses enhanced the basal synthesis of 5-HETE and LTB4 as well. Under stimulated conditions, enhanced glomerular production of 5-HETE and LTB4 occurred at 15 min after infusion of anti-GBM Ig, peaked at 1 h, and returned toward control levels by 24 h. At 48 h, 72 h, and on day 12, the synthesis of these eicosanoids was impaired. Neutrophile depletion only partially reduced glomerular eicosanoid synthesis after induction of NSGN whereas complement depletion significantly reduced 5-HETE, 12-HETE, and LTB4. These observations indicate that in the heterologous phase of NSGN there is enhanced but short-lived glomerular 5-HETE and LTB4 synthesis. This phenomenon is mediated by complement activation and may be an important proinflammatory event leading to capillary wall injury in the early stages of the disease.