Dopamine D₁-like receptors regulate the α_1A-adrenergic receptor in human renal proximal tubule cells and D₁-like dopamine receptor knockout mice

Abstract

The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D₁-like dopamine receptors [dopamine D₁ and D₅ receptors (D₁Rs and D₅Rs, respectively)] and the α₁A-adrenergic receptor (α₁A-AR) are expressed in the renal proximal tubule and engender opposing effects on Na(+) transport, i.e., natriuresis (via D₁Rs and D5Rs) or antinatriuresis (via α₁A-ARs). We tested the hypothesis that the D₁R/D₅R regulates the α₁A-AR. D₁-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with α₁A-ARs in lipid rafts in immortalized human renal proximal tubule cells. Long-term treatment with the D₁R/D₅R agonist fenoldopam resulted in decreased D₁R and D₅R expression but increased α₁A-AR abundance in the plasma membrane. Short-term fenoldopam treatment stimulated the translocation of Na(+)-K(+)-ATPase from the plasma membrane to the cytosol that was partially reversed by an α₁A-AR agonist, which by itself induced Na(+)-K(+)-ATPase translocation from the cytosol to the plasma membrane. The α₁A-AR-specific agonist A610603 also minimized the ability of fenoldopam to inhibit Na(+)-K(+)-ATPase activity. To determine the interaction among D₁Rs, D₅Rs, and α₁A-ARs in vivo, we used phenylephrine and A610603 to decrease Na(+) excretion in several D1-like dopamine receptor knockout mouse strains. Phenylephrine and A61603 treatment resulted in a partial reduction of urinary Na(+) excretion in wild-type mice and its abolition in D1R knockout, D₅R knockout, and D₁R-D₅R double-knockout mice. Our results demonstrate the ability of the D₁-like dopamine receptors to regulate the expression and activity of α₁A-AR. Elucidating the intricacies of the interaction among these receptors is crucial for a better understanding of the crosstalk between anti- and pro-hypertensive systems.

Sorting nexin 1 loss results in increased oxidative stress and hypertension

“…Second, the renal D 5 R regulates BP by promoting the proteasomal degradation of the hypertensinogenic AT 1 R, 8 in addition to its degradation via the lysosomes, as part of normal receptor turnover. Third, the D 5 R, in conjunction with the D 1 R, suppresses the expression and activity of the α 1A ‐adrenoceptor (α 1A ‐AR), 31 a receptor with anti‐natriuretic and hypertensinogenic properties. Fourth, renal D 5 R prevents oxidative stress by suppressing pro‐oxidant activity (eg, NOX expression and activity) and enhancing antioxidant activity (eg, HO‐1) 6,25 .…”

“…However, none of the SNX1 variants is associated with BP response to the β 1 adrenoceptor antagonist atenolol. The interaction of the D 1 ‐like receptors with the β 1 ‐adrenergic receptor has not been described, although both D 1 R and D 5 R interact with the α 1A ‐adrenergic receptor in hRPTCs and kidneys of mice 31 …”

The Role of the Renal Dopaminergic System and Oxidative Stress in the Pathogenesis of Hypertension

“…The D 1 R also decreases renal ion transport by interacting with natriuretic hormones and receptors and antinatriuretic hormones and receptors. Thus, the D 1 R adds to the inhibitory effect on ion transport caused by natriuretic hormones, such as angiotensin 1–7 [ 168 ], atrial natriuretic peptide [ 169 ], and prolactin [ 170 ], and receptors such as the angiotensin II type 2 receptor (AT 2 R) [ 171 ], and gastrin/cholecystokinin B receptor (CCKBR) [ 172 ] but decreases the stimulatory effect of renal ion transport caused by angiotensin II (Ang II) [ 166 , 173 ] and α1-adrenergic receptor [ 33 ].…”

“…This effect is impaired in the SHR [ 222 ]. As with the D 1 R, the D 5 R also decreases renal ion transport by adding to or enhancing the natriuretic effect of hormones and receptors, such as gastrin/CCKBR [ 251 ] and antagonizing the effect of antinatriuretic hormones and receptors, such as AT 1 R [ 252 , 253 , 254 ] and α-adrenergic receptors [ 33 ]. The D 1 R and D 5 R interact to inhibit NHE3 and Na + /K + -ATPase activity in human renal proximal tubule cells via the phospholipase C pathway [ 165 ].…”

“…The increase in urinary dopamine is associated with an increase in sodium excretion [ 31 ]. By contrast, fava bean, which increases urinary dopamine and urinary norepinephrine, does not increase sodium excretion [ 32 ], probably because norepinephrine antagonizes the ability of dopamine to inhibit renal sodium transport [ 33 ]. It should be noted, however, that the L-DOPA content of fava bean is 1/10 that of fava bean seedlings [ 31 ].…”