TY - JOUR
T1 - Role of endogenous CYP450 metabolites of arachidonic acid in maintaining the glomerular protein permeability barrier
AU - Williams, Jan Michael
AU - Sharma, Mukut
AU - Anjaiahh, Siddam
AU - Falck, J R
AU - Roman, Richard J.
PY - 2007/8
Y1 - 2007/8
N2 - 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 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-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MSPPOH; 5 μM), on Palb. 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 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.
AB - 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 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-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MSPPOH; 5 μM), on Palb. 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 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.
KW - 20-hydroxyeicosatetraenoic acid
KW - Epoxyeicosatetraenoic acids
KW - Glomerular permeability to albumin
KW - Glomeruli
KW - HET0016
KW - N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide
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UR - http://www.scopus.com/inward/citedby.url?scp=34548435752&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00131.2007
DO - 10.1152/ajprenal.00131.2007
M3 - Article
C2 - 17507602
AN - SCOPUS:34548435752
SN - 1931-857X
VL - 293
SP - F501-F505
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 2
ER -