TY - JOUR
T1 - Arachidonic acid metabolites inhibit the stimulatory effect of angiotensin II in renal proximal tubules
AU - Li, Yuehong
AU - Yamada, Hideomi
AU - Kita, Yoshihiro
AU - Suzuki, Masashi
AU - Endo, Yoko
AU - Horita, Shoko
AU - Yamazaki, Osamu
AU - Shimizu, Takao
AU - Seki, George
AU - Fujita, Toshiro
PY - 2008
Y1 - 2008
N2 - 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-α-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-α/P450/EET pathway blocks the stimulatory effect of Ang II by suppressing the ERK activation. Thus, the cPLA2-α/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.
AB - 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-α-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-α/P450/EET pathway blocks the stimulatory effect of Ang II by suppressing the ERK activation. Thus, the cPLA2-α/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.
UR - http://www.scopus.com/inward/record.url?scp=61949339292&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=61949339292&partnerID=8YFLogxK
U2 - 10.1291/hypres.31.2155
DO - 10.1291/hypres.31.2155
M3 - Article
C2 - 19139605
AN - SCOPUS:61949339292
VL - 31
SP - 2155
EP - 2164
JO - Hypertension Research
JF - Hypertension Research
SN - 0916-9636
IS - 12
ER -