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  • The ETB receptor has been shown to

    2021-09-15

    The ETB receptor has been shown to decrease sodium transport in the renal medullary collecting duct and medullary thick ascending limb of Henle10, 11, 12, 13, 18. However, both inhibitory and stimulatory effects of endothelin have been reported in the proximal tubule16, 47, 48, 49. In the rat, endothelin acutely inhibits fluid and bicarbonate transport by reducing Na+/K+ adenosine triphosphatase (ATPase) activity[17]. Short-term stimulation of ETB receptors in opossum kidney cells, a renal proximal tubular cell line, activates the sodium hydrogen exchanger, NHE3[50]. However, chronic treatment of the same opossum kidney nkh receptor by endothelin has an opposite effect on NHE3 activity[15]. Thus, a 6-hour exposure of opossum kidney cells to endothelin-1 inhibits NHE3 expression and activity[15]. It is of interest that the ability of an ETB receptor agonist to decrease AT1 receptor expression also occurs within the same time frame as the ability of ETB to inhibit NHE3 expression and activity. Another G protein-coupled receptor, the D3 dopamine receptor has been shown to inhibit NHE3 activity in rat renal proximal tubules and immortalized rat renal proximal tubule cells[51]. We have preliminary data showing that the acute (2 hours) natriuretic effect of a D3 receptor agonist, PD128907, can be blocked by an ETB receptor antagonist, BQ788 [Zeng C,et al, unpublished data, 2004]. These preliminary results could be taken to indicate that the ETB receptor can regulate sodium transport in the renal proximal tubule, in vivo, by interacting with the D3 receptor. These studies provide evidence for a potential interaction between the ETB and AT1 receptor, in vivo. We now report that short-term (15 minutes) BQ3020 treatment increases AT1 receptor phosphorylation in WKY renal proximal tubule cells. The ability of ETB receptors to decrease AT1 receptor expression and to increase its phosphorylation[36] would be in keeping with a counterregulatory effect of ETB receptors on AT1 receptor action on renal tubular sodium transport. The decrease in AT1 receptor phosphorylation with BQ3020 in SHR renal proximal tubule cells could participate in the enhanced AT1 receptor-mediated sodium reabsorption in hypertension. Direct proof of this action needs to be shown, however. The mechanism of the decrease in AT1 receptors caused by ETB receptors was not studied. However, we find that short-term stimulation of the ETB receptor increases AT1 receptor phosphorylation in WKY cells; phosphorylation has been reported to prompt AT1A receptor desensitization and internalization[36],[52]. The importance of G protein-coupled receptor kinase (GRK) in regulating G protein-coupled receptor function, including the AT1 and ETB receptors, has been the subject of several reviews53, 54, 55. The AT1 receptor is regulated by casein kinase 1α and GRK254, 55, 56. We have reported that GRK2, to a lesser extent, and GRK4, to a greater extent, regulates the D1 dopamine receptor[57]. We have found that GRK4 serine phosphorylates and inactivates the D1 dopamine receptor[58]. In a preliminary communication, we reported that there is a negative counter regulation of D1 receptor and GRK4 expression [abstract; Felder RA,et al,Hypertension 42:438, 2003]. GRK4 may also regulate the ETB receptor because ETB receptor expression in renal cortex is higher and ETB receptor phosphorylation is lower in GRK4 A142V transgenic mice [Zeng C,et al, unpublished data, 2004]. It is possible that there is also negative regulation between ETB receptor and GRK4, and that the ETB receptor may regulate the AT1 receptor via GRK4. The interaction between ETB and AT1 receptors is rat strain dependent. Our previous study in renal proximal tubule cells indicates that long-term activation (hours) of the AT1 receptor decreases AT1 receptor expression and increases ETB receptor expression in WKY cells. In contrast, in SHRs, AT1 receptor activation increases AT1 receptor expression without affecting ETB receptor expression [abstract; Zeng C,et al,Hypertension 26:80A, 2003]. In this study, we find that long-term activation of the ETB receptor decreases AT1 receptor expression and increases ETB receptor in WKY renal proximal tubule cells but has no effect on either ETB or AT1 expression in SHRs. We now report that AT1 and ETB receptors colocalize in WKY renal proximal tubule cells [abstract; Zeng C,et al,Hypertension 26:80A, 2003]. These two receptors directly interact with each other because they coimmunoprecipitate and activation of AT1 receptor increases AT1/ETB coimmunoprecipitation in WKY but not in SHR cells [abstract; Zeng C,et al,Hypertension 26:80A, 2003]. In the current study, ETB receptor activation does not affect AT1 and ETB receptor coimmunoprecipitation in WKY but decreases it in SHR cells. We now also report that short-term (minutes) activation of ETB receptors increases the serine phosphorylation of the AT1 receptor in WKY cells, but decreases it in SHR cells. The decrease in AT1/ETB receptor coimmunoprecipitation in renal proximal tubularRPT cells following ETB receptor agonist stimulation could not have been caused by the changes in the expression of either ETB or AT1 receptors, because the duration of stimulation is too short (15 minutes) to be caused by changes in receptor expression. However, the results in immortalized renal proximal tubule cells need to be confirmed in freshly isolated renal proximal tubule cells. Whereas the expression and transduction of the D1 dopamine receptor signal is similar in freshly isolated and immortalized renal proximal tubule cells22, 23, 24, 25, this may not be the case for other G protein-coupled receptors (e.g., D3 receptor[59]). Given this caveat, our studies suggest that the activation of the ETB receptor results in its modification or action on some adapter protein(s) that links AT1 and ETB receptors. Moreover, this interaction is different between WKY rats and SHRs. It is possible that the dissociation of ETB receptors from AT1 receptors after ETB receptor stimulation allows these receptors to exert their actions separately. The inability of ETB receptors to decrease AT1 receptor expression in renal proximal tubule of SHRs and a failure to decrease ETB/AT1 receptor heterodimerization could lead to increased AT1 receptor function. The ETB receptor-induced decrease in the phosphorylation of the AT1 receptor in SHR cells may also increase AT1 receptor activity[36]. Renal tubular AT1 receptor action is enhanced in SHRs7, 60, 61, 62.