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  • In a preliminary communication we showed

    2021-11-26

    In a preliminary communication, we showed that AT and ETB receptors colocalize and coimmunoprecipitate in renal proximal tubule cells, and stimulation of the AT receptor increases ETB receptor expression in Wistar-Kyoto (WKY) rats [abstract; Zeng C,, 26:80A, 2003]. We hypothesize that the ETB receptor may also regulate the AT receptor, including its expression. In the current study we examined the interaction between AT and ETB receptors in immortalized rat renal proximal tubule cells, which have characteristics similar to freshly obtained renal proximal tubule PIK-75 australia membranes and renal proximal tubules, at least with regard to D receptors and their responses to G protein stimulation, , , . We now report that long-term activation of the ETB receptor decreases AT receptor and increases ETB receptor expression in renal proximal tubule cells from WKY rats. In contrast, in the spontaneously hypertensive rat (SHR), the ETB receptor has no effect on AT receptor expression. ETB receptor activation does not influence AT and ETB receptor coimmunoprecipitation in WKY cells, but decreases it in SHR cells. Short-term treatment with the ETB agonist, BQ3020, increases phosphorylation of the AT receptor in WKY cells, but decreases it in SHR cells. We conclude that ETB receptors regulate AT receptors by direct physical receptor interaction and receptor expression. The role of ETB regulation of AT receptor expression and phosphorylation on renal proximal tubule ion transport, however, remains to be determined. METHODS
    RESULTS
    DISCUSSION The renin-angiotensin-aldosterone system and the endothelin system are two important systems that regulate blood pressure and renal sodium excretion. Recent studies indicate that angiotensin II may exert some of its effects via an interaction with the endothelin system. Thus, angiotensin II has been reported to increase endothelin-1 synthesis in the kidney[19] and expression of endothelin-converting enzyme-1 in human umbilical vein endothelial cells[37]. The hypertrophic and mitogenic effects of angiotensin II may also be augmented by endothelin, via ETA receptors[38]. Endothelin, via ETA receptors, may also act as an amplifier of the vasoconstrictor effect of angiotensin[39]. There is reciprocal regulation between the two systems. Endothelin-1 has been reported to decrease renin secretion[21]. Endothelin may regulate not only the hemodynamic effects of angiotensin II but also the pathologic consequences of increased activity of the renin-angiotensin-aldosterone system. For example, the hypertension associated with chronic angiotensin II infusion can be attenuated by an ETA/ETB receptor antagonist[19],[20]. In a canine model of Page (kidney wrapping) hypertension, bosentan, a combined ETA and ETB receptor antagonist, exerts a hypotensive effect in addition to that caused by the AT1 receptor antagonist losartan[40]. However, there are no reports on the ability of ETB receptors to regulate AT1 receptor expression. We have reported that ETB and AT1 receptors interact in rat renal proximal tubule cells [abstract; Zeng C,et al,Hypertension 26:80A, 2003]. Our current studies support our previous report that ETB and AT1 receptors can regulate each other at the protein and cell biologic level [abstract; Zeng C,et al,Hypertension 26:80A, 2003]. The interaction among G protein-coupled receptors can be synergistic, additive, or negative. The regulation may occur at the physiologic level where one functional effect antagonizes the other. In the case of the AT1 receptor, its vasoconstrictor effect can augment the ability of ETA and ETB to contract vascular smooth muscle cells[41],[42]. The increase in renal tubular sodium transport caused by AT1 receptors can augment a similar effect of ETA receptors. However, the ability of ETB receptors to stimulate vasodilatory agents from endothelial cells would be counter regulatory43, 44, 45, 46, as would be the ability of renal tubular ETB receptors to decrease sodium transport10, 11, 12, 13, 18.