Dopamine and Angiotensin Type 2 Receptors Cooperatively Inhibit Sodium Transport in Human Renal Proximal Tubule Cells

Abstract

Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinatriuresis) to a state where sodium and water are eliminated (natriuresis). In human renal proximal tubule cells (RPTCs), sodium reabsorption is decreased by the dopamine D1-like receptors (D1R/D5R) and the angiotensin type 2 receptor (AT2R), while the angiotensin type 1 receptor increases sodium reabsorption. Aberrant control of these opposing systems is thought to lead to sodium retention and subsequently hypertension. We show that D1R/D5R stimulation increased plasma membrane AT2R 4-fold via a D1R-mediated, cAMP-coupled, and PP2A-dependent specific signaling pathway. D1R/D5R stimulation also reduced the ability of angiotensin II to stimulate phospho-ERK, an effect that was partially reversed by an AT2R antagonist. Fenoldopam did not increase AT2R recruitment in RPTCs with D1Rs uncoupled from adenylyl cyclase, suggesting a role of cAMP in mediating these events. D1Rs and AT2Rs heterodimerized and cooperatively increased cAMP and cGMP production, PP2A activation, sodium-potassium-ATPase internalization and sodium transport inhibition. These studies shed new light on the regulation of renal sodium transport by the dopaminergic and angiotensin systems and potential new therapeutic targets for selectively treating hypertension.

Altered signaling pathways linked to angiotensin II underpin the upregulation of renal Na+-ATPase in chronically undernourished rats

“…It is clear that undernutrition affects signaling pathways selectively. Thus, it is possible that undernutrition also affects the regulatory phosphorylations that have been demonstrated for (Na + + K + )ATPase [43,50,55], as well as those that depend of interactions on the dopaminergic system with RAS [56][57][58]. Besides the local renal RAS, it is also clear that undernutrition simultaneously alters the circulatory, cardiac and brain RAS, facing the increased catecholamine levels [1,59], accentuated hypertension [60] and structural and electric cardiac remodeling [5].…”

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

“…In conclusion, in salt-resistant normotensive humans on HS diets, fenoldopam causes natriuresis by inhibiting proximal and distal tubular sodium transport, 21,22,24,31,32,34 similar to the effects of low doses of dopamine in humans. 24 The absence of natriuresis in response to fenoldopam during modest salt restriction compared to its robust natriuretic effect during salt loading may be attributed, in part, 67 to increased RAS activity suggested by the increased percentage effect in response to fenoldopam and enalapril, compared with fenoldopam alone, on a LS diet.…”

“…[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.…”

“…[24][25][26][27][28] Dopamine can also negatively regulate renin production, 29 while angiotensin II (AT 2 ) can increase dopamine turnover. 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.…”