Role of 20-HETE in D1/D2 dopamine receptor synergism resulting in the inhibition of Na+,K+-ATPase activity in the proximal tubule

KIRCHHEIMER, C; MENDEZ, CF; ACQUIER, A; NOWICKI, S

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY - (Print)

The American Physiology Society

Lugar: Bethesda; Año: 2007 vol. 292 p. 1435 - 1442

0363-6127

Previous studies propose 20-hydroxyeicosatetraenoic acid (20-HETE), a major arachidonic acid metabolite of Cytochrome P-450 (CYP), as a possible mediator of Na(+),K(+)-ATPase inhibition by Dopamine (DA). The aim of this study was to investigate the intracellular mechanisms involved in this effect and to elucidate the DA receptor associated with the 20-HETE pathway in the rat kidney. DA (10(-5) M) inhibited Na(+),K(+)-ATPase activity in microdissected tubular segments to 59.4+/-3.8% of control activity. This response was suppressed by the CYP4A inhibitor 17-octadecynoic acid (10(-6) M), which had no effect per se, thus confirming the participation of CYP arachidonic acid metabolites in DA-induced Na(+),K(+)-ATPase inhibition. We next examined whether 20-HETE is involved in the signaling pathways triggered by either D1 or D2 receptors. Neither fenoldopam nor quinpirole (D1 and D2 agonists respectively, both 10(-5)M) modified Na(+),K(+)-ATPase activity when tried alone. However, coincubation of a threshold concentration of 20-HETE (10(-9)M) with fenoldopam resulted in a synergistic inhibition of Na(+),K(+)-ATPase activity (66+/-2% of control activity), while 20-HETE plus quinpirole had no effect. Furthermore, 20-HETE (10(-9)M) synergized with forskolin (10(-5)M) and with the diacylglycerol analog 1-oleoyl-2-acetoyl-sn-glycerol (OAG, 10(-11)M) (62.0+/-5.3 and 69.9+/-2.0% of control activity respectively), indicating a cooperative role of 20-HETE with the D1-triggered pathways. In line, no additive effect was observed when OAG and 20-HETE were combined at concentrations which per se produced maximal inhibition (10(-6) M). These results demonstrate that the inhibition of Na(+),K(+)-ATPase activity by DA in the proximal tubule may be the result of the synergism between 20-HETE and the D1 signaling pathway. Key words: Na+,K+-ATPase, dopamine, 20-HETE, proximal tubule.