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Am J Physiol Renal Physiol (May 16, 2007). doi:10.1152/ajprenal.00131.2007
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Submitted on March 20, 2007
Accepted on May 9, 2007

Role of Endogenous CYP450 Metabolites of Arachidonic Acid in Maintaining the Glomerular Protein Permeability Barrier

Jan Michael Williams1, Mukut Sharma2, Siddam Anjaiahh3, John R. Falck3, and Richard J. Roman4*

1 Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Biochemistry, UT Southwestern Medical Center @ Dallas, Dallas, Texas, United States
4 Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States; Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States; Kidney Disease Center, United States

* To whom correspondence should be addressed. E-mail: rroman{at}mcw.edu.

This study examined the metabolism of arachidonic acid (AA) by cytochrome P450 (CYP) enzymes in isolated glomeruli and the effects of selective inhibitors of the synthesis of 20-HETE and EETs on glomerular permeability to albumin (Palb). Glomeruli avidly produced 20-HETE, EETs, DiHETEs, and HETEs when incubated with exogenous AA. N-hydroxy-N`-(4-butyl-2methylphenyl) formamidine (HET0016, 10 µM) selectively inhibited the formation of 20-HETE by 95% and increased Palb 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 Palb (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-methylsulphonyl-6-(2-propargyloxyphenyl) hexanamide (MSPPOH, 5 µM), on Palb. MSPPOH (5 µM) significantly increased Palb 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 Palb. 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.




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