Lipoxygenase products are synthesized in the kidney. Rabbit medulla and murine and human glomeruli produce 12- and 15-hydroxy-5,8,10,14-eicosatetraenoic
acid (
HETE). Minor amounts of
leukotrienes are formed under normal conditions, but it is likely that the resident renal cells are capable of synthesizing these metabolites. Rat glomeruli and papillae possess the
enzymes necessary to process
leukotriene C4 into
leukotrienes D4 and E4. However, the
enzyme activity of the papillae is masked due to the presence of an inhibitor detected in the 10,000 g supernate of the papillary homogenate.
12-HETE synthesis is markedly increased in glomeruli from rats with nephrotoxic serum
nephritis and
leukotriene B4 synthesis in glomeruli from rats with cationic bovine
gamma-globulin-induced
glomerulonephritis. In vivo consequences of the association between the resident glomerular cells and the bone marrow-derived cells have been studied in vitro in co-incubation experiments. Glomeruli release factors that stimulate the
cyclo-oxygenase and
lipoxygenase pathways in macrophages. Co-incubation of glomeruli, platelets, and polymorphonuclear leukocytes results in the formation of
12,20-diHETE and an excess of
12-HETE.
Lipoxygenase products, regardless of their origin, modify the renal functions.
Leukotriene C4 binds specifically to rat glomeruli and human cultured glomerular epithelial cells.
Leukotrienes C4 or D4 administered in vivo cause renal vasoconstriction and a decline in the glomerular filtration rate. In vitro, these two sulfidopeptide
leukotrienes promote epithelial cell proliferation and produce mesangial cell contraction. The
lipoxygenase pathway is also implicated in the attachment of macrophages to glomeruli and in the oxidative burst of glomerular mesangial cells during phagocytosis. The future use of specific inhibitors of the synthesis or antagonists of the
lipoxygenase products, particularly the
leukotrienes, should provide a tool for evaluating the role of these metabolites in renal diseases.