Inhibition of 5-lipoxygenase activating protein decreases proteinuria in diabetic rats

The binding of 5-lipoxygenase (5-LO) to the 5-LO activating protein (FLAP) is a prerequisite for subsequent formation of leukotrienes (LT) from arachidonic acid. We have shown that FLAP antagonist administration decreased proteinuria in glomerulonephritic patients. In this follow-up study, we assessed the role for FLAP in a rat model of streptozotocin-induced diabetic nephropathy. Diabetic rats were treated for 4 weeks with FLAP (BAY X-1005, 200 mg/kg) or 5-LO (Zileuton, 80 mg/Kg) antagonists. Proteinuria, renal function and LT production was assessed. We also determined protein permeability of cultured glomerular endothelial cells (which possess no 5-LO) by measuring their permeability to radiolabeled albumin with and without FLAP antagonists. FLAP mRNA levels increased dramatically in glomeruli from diabetic animals compared to controls. Inhibition of FLAP (but not inhibition of 5-LO) reduced proteinuria, with no effect on estimated glomerular filtration rate. Interestingly, diabetes-induced rises in urinary excretion and glomerular production of leukotrienes were not modified by the inhibitors. Increased FLAP expression in glomerular endothelial cells in culture was associated with an increase in albumin permeability, and this increase was abolished by FLAP antagonists. On the other hand, addition of LTA(4) led to increases in leukotriene formation and in permeability. This increase in permeability was also reduced by co-incubation with FLAP antagonists, whereas the increase in leukotriene synthesis was not modified. These results suggest a role for FLAP other than the activation of 5-LO, possibly in protein handling, and point to FLAP antagonists as anti-proteinuric agents.