Negative reciprocity between angiotensin II type 1 and dopamine D1 receptors in rat renal proximal tubule cells

Abstract

Sodium excretion is bidirectionally regulated by dopamine, acting on D1-like receptors (D1R) and angiotensin II, acting on AT1 receptors (AT1R). Since sodium excretion has to be regulated with great precision within a short frame of time, we tested the short-term effects of agonist binding on the function of the reciprocal receptor within the D1R-AT1R complex in renal proximal tubule cells. Exposure of rat renal proximal tubule cells to a D1 agonist was found to result in a rapid partial internalization of AT1R and complete abolishment of AT1R signaling. Similarly, exposure of rat proximal tubule cells and renal tissue to angiotensin II resulted in a rapid partial internalization of D1R and abolishment of D1R signaling. D1R and AT1R were, by use of coimmunoprecipitation studies and glutathione-S-transferase pull-down assays, shown to be partners in a multiprotein complex. Na ϩ -K ϩ -ATPase, the target for both receptors, was included in this complex, and a region in the COOH-terminal tail of D1R (residues 397-416) was found to interact with both AT1R and Na ϩ -K ϩ -ATPase. Results indicate that AT1R and D1R function as a unit of opposites, which should provide a highly versatile and sensitive system for short-term regulation of sodium excretion.AT 1 receptors; Na ϩ -K ϩ -ATPase; calcium signaling RENAL SODIUM EXCRETION IS bidirectionally regulated by angiotensin II (ANG II) and dopamine (13). Long-term dopamine exposure is known to decrease AT 1 receptors (AT1R) in renal proximal tubular cells (7). Furthermore, studies by Zeng et al. (21) have shown that long-term stimulation of AT1R results in an upregulation of D1-like receptors (D1R). This effect was not observed in spontaneously hypertensive rats, indicating that the interaction between AT1R and D1R has an impact on blood pressure regulation. Since sodium excretion must be regulated with great precision over a short period of time, it is important that control mechanisms are able to exert their effects within a short time frame. The aim of the current study has been to explore the short-term effects of ANG II exposure on D1R and the short-term effects of a D1-agonist on AT1R. Our approach has been to test the hypothesis that AT1R and D1R form a heteromeric signaling complex, where activation of either receptor may cause internalization and/or interruption of the signaling capacity of the other.The studies were performed using rat proximal tubule cells, since these cells express both AT1R and D1R in both the apical and the basolateral membrane (12,18). Previous studies from our laboratory have shown that in these cells Na ϩ -K ϩ -ATPase, the enzyme responsible for active sodium transport, is bidirectionally regulated by ANG II and dopamine (2). MATERIALS AND METHODS Cells and tissue.All studies were performed using outer cortical tissue from young (3-5 wk) male Sprague-Dawley rats. Immediately after the animals were killed, 250-m slices were taken from the outer renal cortex using a microtome. The outer 250-m region of the rat renal cortex contains Ͼ90% proxi...

Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

“…La dopamina renal es uno de los principales reguladores de la excreción de sodio renal con efectos natriuréticos y diuréticos (37). En forma similar a la dopamina, los péptidos del sistema renina-angiotensina-aldosterona RAS, contribuyen de manera importante a la regulación de la homeostasis del sodio por medio de los receptores AGTR1 y AGTR2, por lo cual se han llevado a cabo varios estudios con el fin de comprender la relación existente entre el sistema dopaminérgico y el sistema RAAS, encontrándose que existe una interacción entre estos factores (87,89). Se ha mostrado que, al envejecer, una exagerada función de los receptores renales AGTR1 está asociada con una disminución en la función del receptor DRD1 y con niveles elevados de presión arterial en modelos de ratón (90).…”

Mitochondrial ATP-sensitive potassium channels enhance angiotensin-induced oxidative damage and dopaminergic neuron degeneration. Relevance for aging-associated susceptibility to Parkinson’s disease

“…Furthermore, the interaction between renin-angiotensin system and dopaminergic system is of particular interest. Several studies have shown an important interaction between dopamine and angiotensin II receptors in peripheral tissues, particularly as regards regulating renal sodium excretion and cardiovascular function (Gildea 2009;Zeng et al 2006;Khan et al 2008). Recent evidence suggests that dopaminergic and renin-angiotensin systems directly counterregulate each other in renal cells (Gildea 2009) and also in the nigrostriatal system (Villar-Cheda et al 2010a), and that abnormal counterregulation between dopamine and angiotensin II plays an important role in degenerative changes Li et al 2008;Rodriguez-Pallares et al 2008).…”

Crosstalk between dopamine receptors and the Na+/K+-ATPase (Review)

“…D 1 and AT 1 receptors are partners in a multiprotein complex. NKA, the target for the two receptors, is included in this complex and a region in the COOH-terminal tail of D 1 receptors (residues 397-416) is found to interact with AT 1 receptors and NKA (89). These studies indicate that AT 1 and D 1 receptors function as a unit of opposites, which provides a highly versatile and sensitive system for short-term regulation of sodium excretion.…”

“…Similarly, in the intestine, the inhibitory action of maximal doses of DA on NKA activity is significantly prevented by coincubation with 5-HT, indicating the presence of a functional antagonism between the two amines in the control of NKA activity (62). Additionally, angiotensin receptor subtypes (AT 1 ) and D 1 receptors function as a unit of opposites, which may provide a highly versatile and sensitive system for short-term regulation of sodium excretion (89). The stimulation of renal AT 1 receptors by angiotensin II (Ang II) delivers signals through the PLC pathway to inhibit extraneuronal DA uptake.…”