Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive heymann nephritis

We assessed the role of leukotrienes (LTs) in Munich-Wistar rats with passive Heymann nephritis (PHN), an animal model of human membranous nephropathy. 10 d after injection of anti-Fx1A antibody, urinary protein excretion rate (Upr) in PHN was significantly higher than that of control. Micropuncture studies demonstrated reduced single nephron plasma flow and glomerular filtration rates, increased transcapillary hydrualic pressure difference, pre- and postglomerular resistances, and decreased ultrafiltration coefficient in PHN rats. Glomerular LTB₄ generation from PHN rats was increased. Administration of the 5-LO activating protein inhibitor MK886 for 10d markedly blunted proteinuria and normalized glomerular hemodynamic abnormalities in PHN rats. An LTD₄ receptor antagonist SK&F 104353 led to an immediate reduction in Upr and to reversal of glomerular hemodynamic impairment. Ia( + ) cells/glomerulus were increased in PHN rats. In x-irradiated PHN rats, which developed glomerular macrophage depletion, augmented glomerular LT synthesis was abolished. Thus, in the autologous phase of PHN, LTD₄ mediates glomerular hemodynamic abnormalities and a hemodynamic component of the accompanying proteinuria. The synthesis of LTD₄ likely occurs directly from macrophages or from macrophage-derived LTA₄, through LTC₄ synthase in glomerular cells.