20-HETE or EETs: which arachidonic acid metabolite regulates proximal tubule transporters and contributes to pressure natriuresis?

A MAJOR FUNCTION OF THE KIDNEY is to maintain body fluid and electrolyte homeostasis. Pressure natriuresis is a renal phenomenon that contributes to the long-term regulation of fluid and electrolyte balance and ultimately arterial blood pressure control. The basic phenomenon is that the kidney increases sodium excretion in response to an increase in renal perfusion pressure. A number of studies have demonstrated that pressure natriuresis involves elevations in renal medullary blood flow and renal interstitial hydrostatic pressure that result in inhibition of tubule sodium transport (8, 21, 27). It is also recognized that proximal tubule Na -K -ATPase activity decreases and the sodium/hydrogen exchanger (NHE3) internalizes from the apical membrane of the proximal tubule in response to an elevation in renal perfusion pressure (16, 28). The connection between the renal hemodynamic changes and the decreased proximal tubule sodium transport is poorly understood. The report by dos Santos et al. (6) in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology provides initial evidence that CYP450 metabolites of arachidonic acid contribute to the decrease in proximal tubule Na -K -ATPase activity and internalization of NHE3. Thus a CYP450 metabolite could be a possible messenger that couples the changes in renal hemodynamics to decreased proximal tubular sodium absorption. CYP450 metabolites of arachidonic acid, 20-hydroxyeicosatraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), have vascular and tubular actions and have been implicated in the control of sodium and water excretion (3, 12, 13, 20, 25). Because of their renal actions, CYP450 metabolites have been implicated in the pressure-natriuretic response. A piece of data implicating a CYP450 metabolite as positively contributing to pressure natriuresis is the chronic treatment of Dahl salt-sensitive (S) rats with inducers of CYP450 enzymes (1, 22). Decreased 20-HETE levels have been purported to be responsible for the blunted pressure natriuresis and salt-sensitive hypertension in the Dahl S rat (1, 20). Genetic and pharmacological manipulation to induce the kidney CYP4A hydroxylase enzyme increases 20-HETE levels and normalizes the pressure-natriuretic relationship as well as lowers blood pressure in the Dahl S rats (20). The importance of salt regulation to stimulate CYP2C enzymes and EETs and maintain body fluid and electrolyte homeostasis has also been demonstrated (13, 18, 29). CYP2C protein expression and urinary EET levels increase in response to a high-salt diet (18, 29). Along these lines, chronic administration of clotrimazole to inhibit epoxygenase enzymes induces hypertension in animals fed a high-salt diet (18). Conversely, acute inhibition of the CYP450 pathway increases papillary blood flow and sodium and water excretion without altering renal blood flow or glomerular filtration rate (30). Although contradictory to a positive role for CYP450 metabolites in the pressure-natriuretic response, this finding is consistent with the antinatriuretic and prohypertensive vascular actions described for 20HETE (12, 20). It has been very difficult to investigate and separate 20-HETE’s antinatriuretic vascular actions and the natriuretic tubular actions given the current methodology. In addition, separating the contribution of epoxygenase and hydroxylase metabolites by chronically inhibiting the CYP450 enzymes has been another major challenge. Nonetheless, dos Santos et al. (6) demonstrate that a CYP450 metabolite contributes to pressure natriuresis by acting at the proximal tubule to decrease sodium transport. The identity of the CYP450 metabolite responsible for inhibiting Na -K -ATPase activity and internalizing NHE3 protein remains unknown. What is the evidence that 20-HETE or EETs contribute to regulation of proximal tubule sodium transport and pressure natriuresis? Unfortunately, the epithelial cell activities of the hydroxylase and epoxygenase metabolites make both 20HETE and EETs viable candidates for contributing to the increase in urinary sodium excretion in response to an increase in renal perfusion pressure. 20-HETE and EETs are produced by the proximal tubule and inhibit sodium reabsorption (13, 20). 20-HETE inhibits renal Na -K -ATPase activity and this appears to be due to stimulation of protein kinase C (PKC) to phosphorylate the -subunit of the Na -K -ATPase (19). 20-HETE has also been shown to inhibit Na /H exchange in cultured proximal tubule cells (20). Likewise, EETs have been reported to inhibit Na /H exchange in cultured rabbit proximal tubule cells and isolated rat proximal tubules (13). Therefore, the possibility remains that 20-HETE and/or EETs are stimulated by an increase in renal interstitial hydrostatic pressure and act at the proximal tubule to increase sodium excretion. Does the involvement of CYP450 metabolites to the pressure-natriuretic response extend beyond the proximal tubule segment? A segment of the nephron that was not evaluated in the current study is the thick ascending limb of the loop of Henle (TALH) segment. Na transport in the TALH segment of the nephron is decreased after elevations in renal perfusion pressure (8). Again, 20-HETE and EETs have actions on TALH cells that would decrease sodium reabsorption (13, 20). 20-HETE appears to be the primary arachidonic acid metabolite produced by TALH cells. Inhibition of the Na -K -2Cl cotransporter by 20-HETE is due to the fact that 20-HETE blocks an apical membrane 70-pS K channel that limits the availability of K for the TALH Na -K 2Cl cotransporter (26). The ability of EETs to inhibit renal epithelial cell Na K -2Cl cotransport has also been established (13). A recent study demonstrated that nitric oxide-mediated inhibition of Na -K -2Cl cotransport in a renal epithelial cell line (MMDD1) involves stimulation of a CYP450 pathway (11). Address for reprint requests and other correspondence: J. D. Imig, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500 (E-mail: [email protected]). Am J Physiol Regul Integr Comp Physiol 287: R3–R5, 2004; 10.1152/ajpregu.00151.2004.