Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion

Abstract

The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects.

Dietary Fructose Increases the Sensitivity of Proximal Tubules to Angiotensin II in Rats Fed High-Salt Diets

“…In contrast to Ang II, atrial natriuretic peptide (ANP) is a major inhibitory hormone of proximal nephron transport [ 43 , 44 ]. Elevated plasma ANP stimulates urinary Na + excretion during volume expansion [ 45 ], such as likely occurs during fructose-induced salt sensitive hypertension, and it enhances urinary Na + excretion in part through actions on the proximal tubule [ 46 ]. Activation of protein kinase C by Ang II blunts the effects of ANP [ 47 , 48 ] and acute fructose treatment enhances the effects of Ang II via protein kinase C when rats are fed a low-salt diet [ 49 ].…”

Alteration of Renal Natriuretic Systems Is Associated with the Development of Hypertension and Precedes the Presence of Renal Damage in a Model of Metabolic Syndrome

“…(30) Our laboratory has shown that ANP stimulates dopamine uptake by tubular kidney cells, through the stimulation of NPRA receptors and protein kinase G (PKG) activation. (11,12,22) Moreover, it has been shown that ANP increases the synthesis of renal dopamine by stimulating the activity of dopa decarboxylase. (31) In this insulin-resistance model, and as a result of low levels of plasma ANP, a reduction in both synthesis and uptake of dopamine by tubular cells would be expected as a consequence of reduced…”

“…Protein expression was semiquantitatively analyzed using western blot technique, as previously described. (22) Renal expression of Na+/K+-ATPase was determined using anti-Na+/K+-ATPase antibody (Amersham, dilution 1: 8000), renal expression of NPRA, using anti-NPRA antibody (Santa Cruz Biotechnology, dilution 1: 7500), and expression of NPRC, using anti-NPRC antibody (Santa Cruz Biotechnology, dilution 1: 400). Biotinylated IgG anti-rabbit antibody (GE Healthcare Life Sciences, dilution 1: 2000) and streptavidin conjugated with radish peroxidase (GE Healthcare Life Sciences, dilution of 1: 2000) were used for secondary and tertiary reactions, respectively.…”

Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney

“…However, the clinical efficacy of dopamine infusion has been questioned by a number of clinical studies that indicate that exogenous dopamine lacks effect on promoting renal sodium and water excretion in pathological conditions [28–33]. In this way, we have recently reported that an alteration in dopamine tubular transport by OCTs may decrease dopamine bioavailability into the lumen and impair the interaction of dopamine with D1 and D2 receptors [34]. Therefore, a full activity of OCTs is not only necessary to elicit dopamine diuretic and natriuretic actions when it is exogenously administered to rats but also necessary for ANP to exert its full diuretic and natriuretic effects [34].…”

“…In this way, we have recently reported that an alteration in dopamine tubular transport by OCTs may decrease dopamine bioavailability into the lumen and impair the interaction of dopamine with D1 and D2 receptors [ 34 ]. Therefore, a full activity of OCTs is not only necessary to elicit dopamine diuretic and natriuretic actions when it is exogenously administered to rats but also necessary for ANP to exert its full diuretic and natriuretic effects [ 34 ]. Based on this evidence, understanding how Ang 1-7 and CNP can regulate dopamine transport by OCTs and dopamine availability in renal tubules provides new knowledge about the mechanisms that could impair the diuretic and natriuretic effects of dopamine when it is therapeutically administered in patients with renal failure.…”