Arachidonic acid metabolites inhibit the stimulatory effect of angiotensin II in renal proximal tubules.
Angiotensin II (Ang II) regulates renal proximal transport in a biphasic way via Ang II type 1 receptor (AT1). Whereas extracellular signal-regulated kinase (ERK) activation mediates the stimulatory effect, cytosolic phospholipase A2 (cPLA2) mediates the inhibitory effect independently of ERK. In this study, we tested the hypothesis that the cPLA2/P450 epoxygenase pathway might work to suppress the Ang II-mediated ERK activation. In the presence of arachidonic acid or 5,6-epoxyeicosatrienoic acid (EET), Ang II failed to stimulate the Na-HCO3 cotransporter activity in renal proximal tubules isolated from wild-type, AT1A-deficient, and cPLA2-alpha-deficient mice. In addition, Ang II failed to induce a significant ERK phosphorylation in the presence of arachidonic acid or 5,6-EET. Arachidonic acid or 5,6-EET also suppressed the stimulatory effect of Ang II on net proximal tubule bicarbonate absorption without changing cell Ca2+ concentrations. These results indicate that the cPLA2-alpha/P450/EET pathway blocks the stimulatory effect of Ang II by suppressing the ERK activation. Thus, the cPLA2-alpha/P450/EET pathway may operate as a unique negative feedback mechanism to attenuate excessive Ang II activity in the renal proximal tubules, where extremely high concentrations of Ang II are found.
Li
Yuehong
Y
Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Yamada
Hideomi
H
Kita
Yoshihiro
Y
Suzuki
Masashi
M
Endo
Yoko
Y
Horita
Shoko
S
Yamazaki
Osamu
O
Shimizu
Takao
T
Seki
George
G
Fujita
Toshiro
T
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D027982:Sodium-Bicarbonate Symporters / Q000187:drug effects / Q000378:metabolism*
D044140:Receptor, Angiotensin, Type 1; D027982:Sodium-Bicarbonate Symporters; D000804:Angiotensin II; D016718:Arachidonic Acid; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D048049:Extracellular Signal-Regulated MAP Kinases; D054513:Group IV Phospholipases A2; D015126:8,11,14-Eicosatrienoic Acid; D002118:Calcium