Mechanisms of Dopamine D ₁ and Angiotensin Type 2 Receptor Interaction in Natriuresis

Abstract

Renal dopamine D1-like receptors (D1R) and angiotensin type-2 receptors (AT2R) are important natriuretic receptors counterbalancing angiotensin type-1 receptor-mediated tubular sodium (Na+) reabsorption. Here we explore the mechanisms of D1R and AT2R interaction in natriuresis. In uninephrectomized, Na+-loaded Sprague-Dawley rats, direct renal interstitial (RI) infusion of highly selective D1R agonist fenoldopam (FEN) induced a natriuretic response that was abolished by AT2R specific antagonist PD-123319 (PD) or by microtubule polymerization inhibitor nocodazole (NOC) but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immuno-electron microscopy, FEN translocated AT2Rs from intracellular sites to the apical plasma membranes (AM) of renal proximal tubule cells (RPTCs) and this translocation was abolished by NOC. Since D1R activation induces natriuresis via an adenylyl cyclase/cyclic adenosine monophosphate (cAMP) signaling pathway, we explored whether this pathway is responsible for AT2R recruitment and AT2R-mediated natriuresis. RI co-infusion of adenylyl cyclase activator forskolin (FSK) and 3-isobutly-1-methylxanthine (IBMX) induced natriuresis that was abolished either by PD or NOC but was unaffected by specific D1R antagonist SCH-23390 (SCH). Co-administration of FSK and IBMX also translocated AT2Rs to the AMs of RPTCs; this translocation was abolished by NOC but was unaffected by SCH. The results demonstrate that D1R-induced natriuresis requires AT2R recruitment to the AMs of RPTCs in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D1Rs and AT2Rs act in concert to promote Na+ excretion in vivo.

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).…”

The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

“…53 Fenoldopam's natriuretic effect on a HS diet is related, perhaps, to decreased proximal and distal sodium transport, as shown previously. 22,24,32 Enalapril did not cause natriuresis on either diet at the dose employed. Higher doses (20 mg) of enalapril cause natriuresis in humans on 10-300 mmol Na + /day but not on 400 mmol Na + /day.…”

“…[18][19][20][21][22][24][25][26]31,32,34,39 Selective gene deletion of aromatic amino acid decarboxylase (essential for renal dopamine synthesis) in the renal proximal tubule in mice produces salt-sensitive hypertension, 43 underscoring the importance of dopamine synthesis by the proximal tubule in sodium homeostasis and BP regulation. Renal dopamine increases with acute and chronic salt loading 44 and acts on D 1 -like 45 and D 2 -like 46 dopamine receptors, causing natriuresis.…”

“…Renal dopamine increases with acute and chronic salt loading 44 and acts on D 1 -like 45 and D 2 -like 46 dopamine receptors, causing natriuresis. [18][19][20][21][22][24][25][26]31,32,34,39 The natriuretic effect of dopamine is impaired in salt-depleted states. 46,47 We submit evidence, for the first time in normotensive (,120/80 mmHg) 48 salt-resistant humans, 33 that the RAS and dopaminergic system interact in regulating renal sodium transport on LS and HS diets.…”

“…30 By contrast, D 1 -like and AT 2 receptors cooperate to inhibit renal proximal sodium transport, 31 causing natriuresis. 32 In the current study, we tested the hypothesis that the previously reported attenuated natriuretic effect of D 1 -like receptor agonists in normotensive humans 22 during salt restriction is caused, in part, by increased RAAS activity. In this double-blind, placebo-controlled, balanced crossover study, we examined the effect of inhibition of the angiotensin converting enzyme with enalapril on the natriuretic effect of D 1 -like receptor stimulation with fenoldopam in salt-resistant normotensive subjects on low-salt (LS) and high-salt (HS) diets.…”