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Role of endogenous CYP450 metabolites of arachidonic acid in maintaining the glomerular protein permeability barrier

Departments of ¹Physiology and ²Medicine, ³Kidney Disease Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and ⁴Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 20 March 2007 ; accepted in final form 9 May 2007

This study examined the metabolism of arachidonic acid (AA) by cytochrome P-450 enzymes in isolated glomeruli and the effects of selective inhibitors of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatetraenoic acids (EETs) on glomerular permeability to albumin (P_alb). Glomeruli avidly produced 20-HETE, EETs, dihydroxyeicosatetraenoic acids (diHETEs), and HETEs when incubated with exogenous AA. N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016; 10 µM) selectively inhibited the formation of 20-HETE by 95% and increased P_alb from 0.00 ± 0.08 to 0.73 ± 0.10 (n = 43 glomeruli, 4 rats). Addition of a 20-HETE mimetic, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (20-5,14-HEDE; 1 µM) opposed the effects of HET0016 (10 µM) to increase P_alb (0.21 ± 0.10, n = 36 glomeruli, 4 rats). Preincubation of glomeruli with exogenous AA to increase basal production of 20-HETE had a similar effect. We also examined the effect of an epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MSPPOH; 5 µM), on P_alb. MSPPOH (5 µM) significantly increased P_alb but had no effect on the synthesis of EETs in glomeruli incubated with AA. However, MSPPOH (5 µM) selectively reduced epoxygenase activity by 50% in glomeruli incubated without added AA. Pretreatment with 8,9-EET (100 nM) attenuated the effects of MSPPOH (5 µM) on P_alb. These results indicate that glomeruli produce 20-HETE, EETs, diHETEs, and HETEs and that endogenously formed 20-HETE and EETs play an essential role in the maintenance of the glomerular permeability barrier to albumin.

glomeruli; HET0016; N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; glomerular permeability to albumin; 20-hydroxyeicosatetraenoic acid; epoxyeicosatetraenoic acids

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