Enhanced renal leukotriene production in murine lupus: Role of lipoxygenase metabolites. To investigate the potential role of leuko-trienes in murine lupus, we measured renal hemodynamics and renal leukotriene production in MRL-lpr/lpr mice at 12 and 20 weeks of age. Over this age range, these animals develop overt manifestations of autoimmune disease with nephritis similar to human SLE. In the current study, we demonstrated that glomerular filtration rate (GFR) and PAH clearance (C_PAH) deteriorated with age in MRL-lpr/lpr mice, but not in MRL-+/+ controls. Impaired renal hemodynamic function in MRL-lpr/lpr mice was associated with enhanced ionophore-stimulated production of both leukotriene B₄ (LTB₄) and leukotriene C₄ (LTC₄) by preparations of renal cortex. There was a significant inverse correlation between GFR and in vitro production of both LTC₄ and LTB₄ in kidneys from MRL-lpr/lprmice, but not in control animals. In addition, in vitro LTC₄ production was correlated with the severity of renal histomorphologic abnormalities. Administration of the specific peptido-leukotriene receptor antagonist SKF104353 to 20 week old MRL-lpr/lpr mice significantly improved both GFR and C_PAH, whereas this agent had no effect of renal hemodynamics in MRL-+/+ controls. These results suggest that renal production of LTC₄ and LTB₄ is increased in MRL-lpr/lpr mice with nephritis, and that enhanced production of peptidoleukotrienes causes reversible renal dysfunction. Increased leukotriene production within the kidney may therefore be important in the pathogenesis of lupus nephritis.