Impaired Stimulatory Effect of ETB Receptor on D₃ Receptor in Immortalized Renal Proximal Tubule Cells of Spontaneously Hypertensive Rats

Abstract

Background: Activation of renal D₃ receptor induces natriuresis and diuresis in Wistar-Kyoto (WKY) rats; in the presence of ETB receptor antagonist, the natriuretic effect of D₃ receptor in WKY rats is reduced. We hypothesize that ETB receptor activation may regulate D₃ receptor expression in renal proximal tubule (RPT) cells from WKY rats, which is impaired in RPT cells from spontaneously hypertensive rats (SHRs). Methods: D₃ receptor expression was determined by immunoblotting; the D₃/ETB receptor linkage was checked by coimmunoprecipitation; Na⁺-K⁺-ATPase activity was determined as the rate of inorganic phosphate released in the presence or absence of ouabain. Results: In RPT cells from WKY rats, the ETB receptor agonist BQ3020 increased D₃ receptor protein. In contrast, in RPT cells from SHRs, BQ3020 did not increase D₃ receptor. There was coimmunoprecipitation between D₃ and ETB receptors in RPT cells from WKY and SHRs. Activation of ETB receptor increased D₃/ETB coimmunoprecipitation in RPT cells from WKY rats, but not from SHRs. The basal levels of D₃/ETB receptor coimmunoprecipitation were greater in RPT cells from WKY rats than in those from SHRs. Stimulation of D₃ receptor inhibited Na⁺-K⁺-ATPase activity, which was augmented by the pretreatment with the ETB receptor agonist BQ3020 in WKY RPT cells, but not in SHR RPT cells. Conclusion: ETB receptors regulate and physically interact with D₃ receptors differently in WKY rats and SHRs. The impaired natriuretic effect in SHRs may be, in part, related to impaired ETB and D₃ receptor interactions.

Enhanced Natriuresis and Diuresis in Wistar Rats Caused by the Costimulation of Renal Dopamine D3and Angiotensin II Type 2 Receptors

“…Consistent with our previous report, 23 the stimulation of D 3 R with PD128907 (10 −10 -10 −7 M, 15 minutes) inhibited Na + -K + -ATPase activity in a concentration-dependent manner, with a significant effect first observed at 10 −8 M, in immortalized RPTCs (Figure 2a). The inhibitory effect of PD128907 (10 −8 M) was specific to the D 3 R because its effect was blocked by the D 3 R antagonist U99194A (10 −5 M) (Figure 2b).…”

Vascular endothelin receptor type B: Structure, function and dysregulation in vascular disease

“…The ability of ET A R antagonist to completely relax ET-1 contraction only in the presence of ET B R antagonist, and vice-a-versa, suggests cross-talk between ET A R and ET B R in the cerebral circulation [32]. ET B R may form heterodimers with other receptors such as the dopamine D3 receptor and angiotensin type 1 receptor (AT 1 R) in the renal proximal tubules [28] [33] [34] [35], and the receptor heterodimerization may play a role in salt and water homeostasis and BP control.…”

Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension

“…D 3 -/mice have an impaired ability to excrete an acute [106] and a chronic sodium load [109]. Moreover, an impaired ability to excrete a NaCl load in genetic hypertension can be explained, in part, by dysfunction of the D 1 R [62,107,115,122,123] and D 3 R [72,82,104,124,125]. The D 3 R, by itself or via its interaction with the D 1 R, is vasodilatory [94] and this effect is impaired in SHRs [97].…”