T. Katoh et al., LEUKOTRIENE D(4) IS A MEDIATOR OF PROTEINURIA AND GLOMERULAR HEMODYNAMIC ABNORMALITIES IN PASSIVE HEYMANN NEPHRITIS, The Journal of clinical investigation, 91(4), 1993, pp. 1507-1515
We assessed the role of leukotrienes (LTs) in Munich-Wistar rats with
passive Heymann nephritis (PHN), an animal model of human membranous n
ephropathy. 10 d after injection of anti-Fx1A antibody, urinary protei
n excretion rate (Upr) in PHN was significantly higher than that of co
ntrol. Micropuncture studies demonstrated reduced single nephron plasm
a flow and glomerular filtration rates, increased transcapillary hydru
alic pressure difference, pre- and postglomerular resistances, and dec
reased ultrafiltration coefficient in PHN rats. Glomerular LTB4 genera
tion from PHN rats was increased. Administration of the 5-LO activatin
g protein inhibitor MK886 for 10 d markedly blunted proteinuria and no
rmalized glomerular hemodynamic abnormalities in PHN rats. An LTD4 rec
eptor antagonist SK&F 104353 led to an immediate reduction in Upr and
to reversal of glomerular hemodynamic impairment. Ia(+) cells/glomerul
us were increased in PHN rats. In x-irradiated PHN rats, which develop
ed glomerular macrophage depletion, augmented glomerular LT synthesis
was abolished. Thus, in the autologous phase of PHN, LTD4 mediates glo
merular hemodynamic abnormalities and a hemodynamic component of the a
ccompanying proteinuria. The synthesis of LTD4 likely occurs directly
from macrophages or from macrophage-derived LTA4, through LTC4 synthas
e in glomerular cells.