Key result
Arachidonic acid and 5,6-EET block Angiotensin II-stimulated Na-HCO3 cotransporter activity via ERK suppression in mice.
Why the study?
The mechanism by which the cPLA2/P450 epoxygenase pathway suppresses Ang II-mediated ERK activation in renal proximal tubules was unclear.
The cPLA2-alpha/P450/EET pathway acts as a negative feedback mechanism to attenuate excessive Angiotensin II activity in renal proximal tubules by suppressing ERK activation.
No change to hypertension care; leaves open EET pathway relevance in human renal 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.
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Li et al. (2008) studied Angiotensin II signaling in renal proximal tubules. Arachidonic acid or 5,6-epoxyeicosatrienoic acid (EET) vs. Control (absence of arachidonic acid or 5,6-EET) was evaluated on Na-HCO3 cotransporter (NBC) activity and ERK phosphorylation (p=<0.01). Arachidonic acid and 5,6-EET blocked the stimulatory effect of Angiotensin II on Na-HCO3 cotransporter activity by suppressing ERK activation in mouse renal proximal tubules.
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