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Review

Role of Renal Dopamine Receptors in the Regulation of Blood Pressure

by
Jian Yang
1,2,* and
Pedro A. Jose
3
1
Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
2
Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
3
Division of Renal Diseases & Hypertension, Departments of Medicine and Pharmacology/Physiology, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2026, 16(4), 532; https://doi.org/10.3390/biom16040532
Submission received: 25 January 2026 / Revised: 27 March 2026 / Accepted: 29 March 2026 / Published: 2 April 2026
(This article belongs to the Special Issue Novel Mechanisms in Renal Blood Pressure Regulation: From Neuropeptides to Angiotensin II and Dopamine Receptors)
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Abstract

Hypertension continues to be a major global public health challenge. Dopamine generated in the kidney is a vital coordinator of sodium homeostasis and blood pressure control. Dopamine exerts its effects by activating its receptors, which are divided into the D1-like receptor family (D1R and D5R) and the D2-like receptor family (D2R, D3R, and D4R). All five dopamine receptor subtypes are differentially expressed along the nephron. Dopamine receptors inhibit the activities and/or expression of renal tubular sodium transporters/exchangers/channels, decrease renal oxidative stress, and interact with other receptors, including angiotensin II receptors. Many studies have demonstrated that renal dopamine receptors play an important role in the regulation of blood pressure. The germline deletion or renal-selective silencing of any of the five dopamine receptor subtypes may impair sodium excretion and increase blood pressure. In addition, renal dopamine receptor expression and/or function are regulated by some factors such as G protein-coupled receptor kinases, oxidative stress, and sorting nexins. In this article, we summarize the role of each dopamine receptor subtype in the pathogenesis of hypertension and discuss the potential regulatory mechanisms of their expression and function. These may lead to the development of novel therapeutic approaches to the prevention and treatment of hypertension.

1. Introduction

Essential hypertension, also known as primary hypertension, is the persistent abnormal increase in systolic blood pressure and/or diastolic blood pressure. It is recognized as one of the leading causes for all-cause morbidity and a significant risk factor for cardiovascular and other diseases, such as stroke and end-stage renal disease [1]. According to the first global report on hypertension of the World Health Organization in 2023, the number of people with hypertension doubled from 650 million in 1990 to 1.3 billion in 2019 [2]. The prevalence of hypertension in low- and middle-income countries increased in both urban and rural areas between 1990 and 2020 [3]. Even in developed countries, such as the US, the prevalence of hypertension among adults is estimated to be 46.7%, which equates to about 122.4 million subjects [4]. Thus, how to prevent and treat hypertension has become a major global public health challenge.
The pathogenesis of hypertension is complex, determined by genetic, lifestyle, and environmental factors that interact to increase blood pressure and cause end-organ damage [5]. It is well-known that aberrant sodium metabolism, causing excessive sodium in the body, is an important risk factor for the occurrence of hypertension. The kidney is a vital organ in the long-term regulation of blood pressure through maintenance of normal sodium homeostasis [6]. The increased sodium retention in hypertension is, at least in part, due to increased activity of renal sodium transporters/exchangers/pump/channels per se and/or the abnormal regulation of sodium transport [7,8]. The maintenance of a normal balance of natriuresis and anti-natriuresis is regulated by endocrine factors. Among these, dopamine, produced in the kidney, as a vital coordinator of sodium homeostasis and blood pressure through an independent intrarenal dopaminergic system, has attracted much attention [9].
Dopamine, also known as 3-hydroxytyramine, plays an essential role as an endogenous neurotransmitter catecholamine in the central nervous system. Moreover, dopamine also exerts physiological functions in other organs, including the artery, stomach/intestine, kidney, liver, and systems, such as the immune system [10,11,12,13]. Among them, the kidney has received considerable attention due to its ability to regulate dopamine production and its local renal effects. Dopamine exerts its effects by activating its five receptors. Many studies have demonstrated that renal dopamine receptors play an important role in the regulation of blood pressure [14,15,16,17]. In this review, we discuss the classification of dopamine receptors and their biological functions in the kidney, summarize the role of each dopamine receptor subtype in the pathogenesis of hypertension, and then discuss the potential regulatory mechanisms on their expression and function. This may promote our understanding of the role of renal dopamine receptors in the regulation of blood pressure and propose novel therapeutic approaches for the prevention and treatment of hypertension.

2. Intrarenal Dopaminergic System

The kidney synthesizes dopamine, independent of renal nerves, and has an intrarenal dopaminergic system. The circulating dopamine concentration is usually in the picomolar range, which is not high enough to activate its receptors. However, dopamine levels in specific segments of the kidney, such as renal proximal tubules (RPTs), can reach high nanomolar concentrations [17]. Unlike neural cells, RPT cells cannot produce the dopamine precursor L-dihydroxyphenylalanine (L-DOPA), and the dopamine produced in the kidney is not converted to norepinephrine because dopamine β-hydroxylase is not expressed in RPT cells [18]. Filtered L-DOPA is taken up by RPT cells via sodium-dependent and sodium-independent amino acid transporters and then metabolized to dopamine by aromatic amino acid decarboxylase (AADC) [19]. The selective deletion of AADC in RPTs in mice reduces intrarenal dopamine levels, increases the expression of renal sodium transporters/exchangers and water channel, including sodium hydrogen exchanger type 3 (NHE3), sodium-bicarbonate cotransporter (NBC), solute carrier family 12, member 1 (NKCC2), solute carrier family 12, member 3 (NCC), and aquaporin 2 (AQP2), and causes salt-sensitive hypertension [20].
The renal tubular synthesis/release of dopamine is regulated by several factors, such as dietary salt and intracellular sodium [21,22]. When dietary salt intake is increased, the intrarenal dopaminergic system is estimated to be responsible for over 50% of the increase in urinary sodium and water excretion. The increase in renal sodium excretion due to dopamine may be, at least in part, caused by inhibition of sodium transporter, exchanger, and pump activities, in the short-term, and a decrease in the expression of several sodium transporters, exchangers, and pumps, in the long-term. However, the generation of dopamine by the kidney and the dopaminergic-mediated natriuretic response to an acute sodium load are impaired in some hypertensive subjects [23]. In addition, animal studies have shown that the inhibition of renal dopamine production by carbidopa, an inhibitor of peripheral dopa decarboxylase, increases the blood pressure of spontaneously hypertensive rats (SHRs), which is accompanied by a decrease in urinary sodium and dopamine excretion [24]. Under physiological states, enhanced sodium intake per se increases the renal generation of dopamine, which may be responsible for the increased urinary sodium excretion or a compensatory response for defective renal dopamine receptors. However, the combination of increased sodium intake and oxidative milieu accelerates renal dopamine oxidation and inflammation, subsequently causing hypertension [25]. These suggest that a dysfunction of the intrarenal dopaminergic system is involved in the pathogenesis of hypertension.

3. Renal Dopamine Receptor Subtypes

In mammals, intrarenal dopamine exerts its physiological effects via a class of cell surface receptors, which belong to the α-group of the rhodopsin-like (Class A) family of seven transmembrane receptor proteins, called G protein-coupled receptors (GPCRs) [26]. Based on their molecular structure and pharmacology, dopamine receptors are divided into two subfamilies: the D1-like and the D2-like receptor families. The D1-like receptors, comprised of dopamine D1 receptor (D1R) and dopamine D5 receptor (D5R) subtypes, couple to stimulatory G-proteins (Gαs and Golf) and stimulate the activity of adenylate cyclase to increase cytosolic cAMP production [27]. The D2-like receptors, composed of dopamine D2 receptor (D2R), dopamine D3 receptor (D3R), and dopamine D4 receptor (D4R) subtypes, couple to inhibitory G proteins (Gαi and Go), and inhibit adenylyl cyclase activity [18].
All five dopamine receptor subtypes are expressed in the mammalian nephron. However, the dopamine receptor subtypes have distinct distributions in the nephron [15]. All five subtypes of the dopamine receptor family are expressed in the RPT. Three dopamine receptor subtypes, D1R, D3R, and D5R, are expressed in the thick ascending limb of Henle. All the dopamine receptor subtypes, except the D2R, are expressed in the distal convoluted tubule. However, the collecting duct expresses all subtypes of the dopamine receptors, except D3R. Currently, studies have shown that all five dopamine receptor subtypes are involved in the regulation of urinary sodium excretion and blood pressure [9,15,18,28,29]. Aberrant expression and/or dysfunction of renal dopamine receptors disturb sodium homeostasis and cause the development of hypertension (Table 1).

4. Renal Dopamine Receptors and Blood Pressure Regulation

4.1. Renal D1R-Mediated Blood Pressure Regulation

4.1.1. Physiological Effects of Renal D1R

The stimulation of D1-like dopamine receptors decreases tubular sodium reabsorption and promotes urinary sodium excretion. The intrarenal infusion of fenoldopam, an agonist of D1-like receptors, induces natriuresis and diuresis in normotensive Sprague–Dawley (SD) rats fed normal or high salt diets [30,31]. During normal sodium intake, the D1-like dopamine receptors are responsible for 50–70% urinary sodium excretion. It is difficult to determine whether the D1R and/or the D5R mediate this effect because there are no available specific ligands that can distinguish the two receptor subtypes (see below). However, it is generally believed that the natriuretic effect of D1-like dopamine receptors in the proximal tubule is primarily attributed to the D1R since the D1R accounts for almost all of the cAMP production after D1-like receptor activation [18]. D1R-specific gene silencing inhibits cAMP accumulation induced by activation of D1-like receptor, whereas either a novel D5R-selective antagonist LE-PM436 or D5R siRNA has no effect on D1-like receptor-mediated increase in cAMP production [32]. Moreover, D1R depletion, using D1R siRNA, blocks the D1-like receptor-dependent inhibition of sodium transport [32]. This is confirmed by renal D1R knockdown. Intrarenal administration of D1R antisense oligonucleotides (AS-ODN) reduces urinary sodium excretion and urine output, but does not affect systolic blood pressure, in female SD rats on a normal or high salt diet [33]. Moreover, global ablation of the Drd1 gene in mice also increases systolic blood pressure [34]. The possible reasons for the heterogeneity of phenotypes of blood pressure may be due to (1) AS-ODN-induced antinatriuresis is short-lasting, which is for only two days on a normal salt diet and three days on a high salt diet. Longer term suppression of the renal D1R may be necessary to show its effect on the regulation of blood pressure; (2) AS-ODN only reduces renal D1R protein by 46% [33]. Complete knockout or more complete suppression of D1R may be needed to change blood pressure; (3) blood pressure was measured by the noninvasive tail-cuff method in AS-ODN studies, but arterial blood pressure was recorded from the femoral artery in D1R knockout mice.
D1-like receptor-mediated natriuretic effect is, at least in part, due to direct inhibition of the activities of renal tubular sodium transporters. The activation of D1-like receptors inhibits the activities of basolateral sodium bicarbonate cotransporter and Na+-K+-ATPase (NKA), and luminal NHE3, sodium phosphate cotransporter type 2 (NaPi2), chloride bicarbonate (Cl-/HCO3-) exchanger, and the epithelial sodium channel (ENaC) [32,35]. These pharmacological studies were confirmed using D1R siRNA, which prevented the inhibition of sodium transport induced by D1-like receptor activation [35]. The D1R-mediated natriuretic effect is also related to its negative regulation of oxidative stress. Stimulation of D1R reduces renal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subsequently inhibits renal oxidative stress [36], which is involved in the positive regulation of sodium transporters and blood pressure [70]. In addition, the renal D1R also interacts with other systems such as the renin-angiotensin-aldosterone system (RAAS) and other renal receptors, including the uroguanylin receptor, angiotensin II (Ang II) receptors, to regulate, cooperatively, urinary sodium excretion and maintenance of sodium homeostasis [37,38,71].

4.1.2. Renal D1R in Hypertension

The human DRD1 gene locus on chromosome 5 at q35.1 is linked to human essential hypertension [72]. DRD1 polymorphism A-48G is associated with essential hypertension in Japanese. Single-nucleotide polymorphisms (SNPs) (rs1799914 and rs4867798) of the DRD1 gene are also associated with hypertension in Hani Chinese [73]. A meta-analysis showed that the rs4532 locus of the DRD1 gene is associated with hypertension in East Asians [74].
Impaired D1R-mediated renal effect is involved in the development of hypertension. The natriuretic and diuretic responses to D1-like receptor agonists are impaired in different animal models of hypertension [39,40,41]. Moreover, the ability of D1-like receptors to inhibit renal sodium transport is also impaired in hypertensive humans [42]. The impaired D1-like receptor function in hypertension may be due, in part, to increased D1R serine phosphorylation and subsequent uncoupling of the D1R from its G protein/effector complex in RPTs [43,44], which leads to the attenuated inhibition of the activity of sodium transporters [75]. Renal D1R expression is also decreased in some animal models of hypertension [45,46,47]. The reduced D1R expression and/or function leads to increased oxidative stress and aberrant interaction between D1R and other receptors, which decreases urinary sodium excretion and subsequently the development of hypertension [37,38,71].

4.2. Renal D2R-Mediated Blood Pressure Regulation

4.2.1. Physiological Effects of Renal D2R

The D2R exerts many physiological functions in the kidneys, including inhibiting sodium transport, suppressing renal inflammation, preventing ischemia/reperfusion injury, and decreasing renal fibrosis [51,76,77,78]. Moreover, D2R synergistically interacts with the renal D1R to increase sodium excretion in SD rats [49]. Although Drd2 knockout mice have increased systolic and diastolic blood pressures, these may not be due to impairment of renal sodium excretion [79]. However, another study found that the global ablation of the Drd2 gene in male mice causes a salt-dependent increase in blood pressure [80]. In addition, in mice, the renal cortical Drd2 depletion with siRNA reduces renal sodium excretion and increases blood pressure, which are reversed by renal-selective D2R rescue [81].
The D2R-mediated sodium excretion is associated with its negative regulation of renal oxidative stress. The D2R decreases renal reactive oxygen species (ROS) production by reducing NADPH oxidase expression and activity and increasing the expression of antioxidant enzymes such as sestrin2 [50]. These indicate that D2R-mediated regulation of oxidative stress involves both pro-oxidant and antioxidant systems. The D2R also regulates renal sodium transport by inhibiting NKA and NHE3. The D2R directly inhibits adenylyl cyclase-mediated cAMP production, which activates NKA [82]. However, the simultaneous stimulation of D1R and D2R is needed for dopamine to inhibit NKA activity in the RPT [48]. Similarly, D1R and D2R synergistically increase NHE-3 phosphorylation, where D2R, by itself, is ineffective [83]. In addition, D2R increases urinary sodium excretion by increasing the synthesis of dopamine in the kidney [51].
It should be noted that D2R has effects in both renal tubules and presynaptic sympathetic ganglia. However, the norepinephrine excretion in Drd2 knockout mice was reduced during the high-salt diet period [80]. This may suggest that the inhibition of sympathetic tone was accompanied by sodium retention and increased blood pressure, which may exclude the possibility that the sympathetic activation is responsible for the high-salt induced changes in sodium balance and blood pressure. In addition, heart rate, another indicator of sympathetic activity, was not different between Drd2 knockout and wild-type (WT) mice. These indicate that the sodium retention and increased blood pressure in Drd2 knockout mice are primarily due to renal tubular dysregulation. However, increased sympathetic activity may also be involved in the D2R-mediated regulation of blood pressure. α-adrenergic blockade decreased blood pressure to a greater extent in Drd2 knockout than WT mice, and epinephrine excretion was greater in Drd2 knockout than WT mice [79]. Moreover, the interaction of the sympathetic nervous system and RAAS is also important in increasing blood pressure levels in Drd2 knockout mice.

4.2.2. Renal D2R in Hypertension

The DRD2 gene is located on chromosome 11, which is linked to human essential hypertension [84]. A TaqI polymorphism of the DRD2 gene is associated with increased blood pressure [85]. Another study showed that a polymorphism in exon 6 of the DRD2 gene is associated with hypertension [86]. The plasma membrane D2R expression is decreased in urine-derived RPT cells isolated from subjects with inverse salt sensitivity, a condition in which a low sodium intake increases blood pressure, relative to those cells isolated from salt-resistant subjects (subjects whose blood pressures are not affected by changes in salt intake), that may be caused by DRD2 variants (rs6276 and 6277) [52]. However, the renal cellular immunolocalization and protein expression of D2R are not different between SHR and WKY rats [61]. Nevertheless, the renal D1-like and D2-like receptor interaction is impaired in SHRs, which causes reduced natriuresis and diuresis [53].

4.3. Renal D3R-Mediated Blood Pressure Regulation

4.3.1. Physiological Effects of Renal D3R

Similar to D1-like and D2 receptors, the activation of renal D3R increases sodium excretion. The intrarenal arterial infusion of PD128907, a D3R agonist, induces natriuresis and diuresis in normotensive rats [58]. In Dahl salt-resistant rats fed either a normal or high-sodium diet, another D3R agonist, 7-hydroxydipropyl-aminotetralin (7-OH-DPAT), also increases urinary sodium excretion. However, although 7-OH-DPAT induces natriuresis in salt-sensitive Dahl rats fed with a normal diet, this does not occur in those fed a high-salt diet [59]. The impaired ability to excrete a sodium load is also present in D3R knockout mice. Disruption of the Drd3 gene in mice increases renal renin levels, and renal Ang II type 1 receptor (AT1R) expression, induces sodium retention, and subsequently causes renin-dependent hypertension [54,56,87]. However, another study reported that male Drd3 knockout mice do not display the hypertensive phenotype regardless of salt intake, although urinary sodium excretion is decreased in these male Drd3 knockout mice fed a high salt diet [88].
The reason that the Drd3 knockout mice show different blood pressure phenotypes may not be due to genetic background, because the Drd3 knockout mice in all four studies are on a C57B1/6J background. Therefore, the possible reasons for the discrepancy among the different studies may be due: (1) sodium protocol: one study used mice on a normal salt diet (0.8% NaCl) [56], one study used a long-term cross-over experiment (low salt diet, 0.2% NaCl; high salt diet, plus 1.0 mg/kg body wt. deoxycorticosterone acetate) [88], and sodium intake was not stated in the other two studies [54,87]; (2) different methods of blood measurement: blood pressure was measured via the femoral vessels in three studies [54,56,87], but tail-cuff plethysmography was used in another study [88]; (3) animal age and sex: the animal age was 3 months in two studies [87,88], but not stated in the other two studies [54,56]; only one study reported that the experiments were performed in male mice [88], but the sex of the animas was not stated in the other studies [54,56,87]; (4) state of consciousness: three studies reported that the mice were anesthetized with pentobarbital (50 mg/kg intravenously) [54,56,87], but another one was performed in conscious mice [88].
D3R-mediated renal sodium excretion is partly attributed to its ability to inhibit renal tubule sodium transport, related to NKA, NHE, and NHE3 [57]. The D3R also regulates the expression of NHE3. Stimulation of D3R inhibits the deubiquitinylating activity of ubiquitin-specific peptidase 48, which promotes NHE3 degradation and subsequently reduces sodium transport; pharmacological blockade of D3R increases renal NHE3 expression [56]. Moreover, the renal D3R is involved in the regulation of renal hemodynamics [60]. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats, the intrarenal medullary blockade of D3R increases mean arterial pressure in parallel with impairment of renal hemodynamics [89]. In addition, renal D3R interacts with other receptors such as other dopamine receptors (i.e., D5R), endothelin B receptor, and Ang II receptors, to maintain a normal sodium homeostasis [54,55,58].

4.3.2. Renal D3R in Hypertension

The chromosome locus of the DRD3 gene (3q13.3) is linked to human essential hypertension [90]. Soma et al. reported that there is no association between the Ser9Gly polymorphism in the D3R gene or other D3R gene variants with hypertension [91]. However, another study showed that SNPs (rs9880168) of the DRD3 are associated with essential hypertension in subjects of Hani nationality, but not in subjects of Han and Yi nationality, in China [92].
Compared with WKY rats, SHRs fed a normal-salt or high-salt diet have reduced D3R expression in the renal cortex and RPT cells [54,61]. There are no differences in D3R expression in the inner medulla of WKY rats and SHRs [61]. However, the D3R agonist PD128907-induced increase in D3R expression is not evident in RPT cells from SHRs [54]. These are reflected by a decrease in D3R physiological actions. The renal D3R-mediated sodium excretion is impaired in SHRs on a normal-salt or on a high-salt diet, relative to WKY rats [58]. In addition, the impaired natriuretic effect induced by activation of D3R in SHRs is also associated with the aberrant interaction of D3R and other receptors [54,55,58].

4.4. Renal D4R-Mediated Blood Pressure Regulation

4.4.1. Physiological Effects of Renal D4R

The stimulation of renal D4R increases urinary sodium excretion in WKY rats [62]. Moreover, renal D4R has been shown to inhibit vasopressin-dependent water and sodium reabsorption in the cortical collecting duct [63,93]. In the rabbit cortical collecting duct, it is the basolateral, not luminal D4R, that is mainly responsible for its natriuretic action [94]. The absence of the Drd4 gene in both male and female mice increases blood pressure by increasing renal AT1R expression [95]. There are no differences in serum aldosterone concentration, plasma renin concentration, and urinary dopamine between Drd4 knockout mice and their littermates [95,96]. Drd4 knockout mice on a normal or high sodium diet have increased blood pressure. The pressure-natriuresis curve is shifted to the right in male Drd4 knockout mice, relative to WT mice. However, low sodium diet decreases blood pressure in both mouse strains [96].
D4R-mediated sodium excretion is partly due to the inhibition of the expression and/or activities of renal tubular sodium transporters. The D4R agonist PD168077 inhibits NKA activity in RPT cells from WKY rats [62]. Drd4 knockout mice on a normal salt diet have increased renal expression of NHE3, NKCC2, NCC, and outer medullary α-ENaC. Moreover, relative to WT littermates, Drd4 knockout mice on a high salt diet have increased expression of sodium transporters in the plasma membrane, which may mediate the salt sensitivity of Drd4 knockout mice [96]. These alterations of the expression of sodium transporters may be due to the ability of D4R to regulate the phosphorylation or degradation of sodium transporters [96,97]. Moreover, renal D4R also interacts with other renal receptors, including AT1R, insulin receptor, and other dopamine receptors, to regulate urinary sodium excretion [62,64,65].

4.4.2. Renal D4R in Hypertension

A locus of the DRD4 gene (11p15.5) is linked to hypertension. The DRD4 gene has a 16 amino acid (48 bp) repeat polymorphism located in exon 3, where a G-protein binding area is encoded. Studies have shown a correlation between an SNP and blood pressure. In a white population with 479 female and 385 male subjects, the long variant of the DRD4 gene is associated with a 3 mm Hg higher systolic and 2 mm Hg higher diastolic blood pressure, relative to non-carriers of the long DRD4 variant [98].
The D4R protein expression is increased in the renal cortex and RPT cells of SHRs, relative to WKY rats. However, there is no difference in the D4R protein expression in the inner medulla between WKY rats and SHRs [61,64]. The phosphorylation of D4R is higher in SHR RPT cells than in WKY cells [62]. Moreover, the D4R-induced diuretic and natriuretic effects are impaired in SHRs, relative to WKY rats [64]. In addition, the aberrant interaction between D4R and other renal receptors is also involved in the impaired urinary sodium excretion and increased blood pressure [62,64,65].

4.5. Renal D5R-Mediated Blood Pressure Regulation

4.5.1. Physiological Effects of Renal D5R

The D5R, which also belongs to the D1-like receptor subgroup, has an 80% homology in its transmembrane domain and a 30% homology in its N and C termini with the D1R [99]. However, D5R has characteristics that are distinct from D1R. For example, D5R has a 10-fold higher affinity for dopamine than D1R; D5R has constitutive activity, which increases the basal activity of adenylyl cyclase [100,101]. These indicate the potential role of renal D5R in the basal regulation of sodium homeostasis and blood pressure.
The role of the renal D5R in the regulation of blood pressure has been verified in Drd5 knockout mice, which have increased systolic and diastolic blood pressures on a normal salt diet [102]. This is further confirmed by cross-transplantation studies. A kidney lacking D5R transplanted into a WT mouse increased systolic and diastolic blood pressures, while a kidney from a WT mouse transplanted into a mouse lacking the D5R decreased blood pressure [66]. These suggest the important role of renal D5R in the regulation of blood pressure. Moreover, the increased blood pressure in Drd5 knockout mice is further increased on a high salt diet, indicating the salt sensitivity of blood pressure in Drd5 knockout mice [66,68,102].
Similar to the other dopamine receptor subtypes, the regulation of blood pressure by the renal D5R is associated with its regulation of renal sodium transport. Activation of D5R by fenoldopam reduces NKA activity in WKY RPT cells with D1R depletion or in D5R-transfected HEK293 cells [55]. Moreover, D5R and D1R, via a D1R/D5R heteromer, synergistically inhibit NHE3 and NKA activities and reduce renal sodium transport [32]. Drd5 knockout mice have higher renal protein expressions of NKCC2, NCC, and ENaC on a normal salt diet, which persist when they are fed a high salt diet [102]. Moreover, the renal protein levels of NHE3 and NaPi2 are also increased in Drd5 knockout mice that are fed a high salt diet [102]. It should be noted that although both D1R and D5R have similar functions, D5R has unique functions distinct from D1R. For example, the increased expression of some renal sodium transporters on a normal salt diet persists, while the high blood pressure is increased further when Drd5 knockout mice are fed a high salt diet [68,102], which is not observed in Drd1 knockout mice. The effects of all five dopamine receptor subtypes modification on renal function and blood pressure are presented in Table 2.
D5R-mediated anti-oxidant stress effect is another important mechanism by which renal D5R regulates blood pressure. D5R directly decreases NADPH oxidase protein expression and activity and inhibits ROS production [68]. These were confirmed in Drd5 knockout mice, which have increased NADPH oxidase protein expression and activity and ROS production [68]. The increased blood pressure and oxidant stress in Drd5 knockout mice are normalized by treatment with apocynin, an NADPH oxidase inhibitor [68]. Cross-transplantation studies between Drd5 knockout and WT mice showed that a kidney from a WT mouse transplanted into a mouse lacking D5R decreases renal NADPH oxidase isoform 2 (NOX2) expression, while a kidney lacking D5R transplanted into a WT mouse increases renal NOX2 expression [66]. D5R exerts its natriuretic effect by other mechanisms. For example, D5R antagonistically interacts with other receptors (e.g., AT1R) to maintain normal blood pressure [69]. The proposed mechanisms by which dopamine receptor subtypes regulate renal function are presented in Figure 1.

4.5.2. Renal D5R in Hypertension

The locus of DRD5, 4p15.1-16.1, is linked to human essential hypertension. D5R SNPs are involved in the regulation of blood pressure. Humans have SNPs in the DRD5 gene, some of which decrease D5R function [103]. The human D5RF173L (hD5RF173L) mutation reduces D5R-mediated cAMP generation. This is reflected in its physiological function; male hD5RF173L transgenic mice have increased blood pressure, which is accompanied by impaired natriuresis and increased renal AT1R expression [67]. These are related to reduced renal expression of Trx1, an antioxidant, and increased renal NADPH oxidase activity and ROS generation [67].
Renal D5R expression is decreased in different hypertensive animal models. Basal D5R levels are reduced in SHR RPT cells and renal brush border membranes of SHRs [69]. There is interaction between D5R and other receptors expressed in the kidney, impairment of which can lead to decreased natriuresis and hypertension [69].

5. Regulation of Renal Dopamine Receptor Expression and Function

5.1. GRK Regulation of Dopamine Receptors

The GPCR kinase (GRK) family has seven members, which are characterized by their ability to recognize and phosphorylate agonist-occupied GPCRs, including dopamine receptors [104,105]. Among the seven GRK subtypes, GRK4 has attracted increased attention because of its important role in the regulation of blood pressure. GRK4 is expressed in only a few tissues, i.e., brain, kidney, myometrium, and testis. GRK4 is well-expressed in the subapical membranes of RPTs and thick ascending limbs of Henle and arteries in both WKY and SHRs [106,107]. GRK4 constitutively phosphorylates GPCRs in the absence of agonist activation [108].
Most current studies on GRK4 have focused on its regulation of D1R. Compared with WKY rats, SHRs have higher basal serine-phosphorylated D1R in RPTs, brush border membranes, and membranes from RPT cells, which are accompanied by greater renal GRK4 expression [16]. The depletion of renal GRK4 with AS-ODN in SHRs increases sodium excretion and urine volume, causes a marked decrease in the increased arterial blood pressure, as well as a decrease in the increased serine-phosphorylated levels of renal D1R [16]. GRK4 silencing completely prevents the serine phosphorylation of D1R and restores fenoldopam-mediated cAMP accumulation in RPT cells from hypertensive subjects [109]. GRK4 expression is increased in obese Zucker rats, which causes hyperphosphorylation of D1R and their uncoupling from Gs proteins [110].
Several GRK4 SNPs, such as R65L, A142V, and A486V, have attracted attention for their important role in the pathogenesis of hypertension. Studies in vitro have shown that GRK4 SNPs increase the basal phosphorylation of D1R and markedly impair the D1R-induced cAMP generation [109]. This is reflected in in vivo studies. Transgenic mice expressing GRK4 A142V are hypertensive, in which the infusion of fenoldopam fails to increase urine flow and sodium excretion [109].
GRK2 is another GRK subtype that is involved in the regulation of renal dopamine receptors [111]. GRK2 expression and/or membranous translocation are increased in RPTs, which increase D1R phosphorylation and cause their uncoupling from signaling proteins in different hypertensive animal models [110,112]. GRK2 siRNA or AS-ODN abrogates D1R serine phosphorylation and normalizes D1R expression and affinity in insulin-treated opossum kidney cells and blunts the desensitization of the D1R in human RPT cells [113].

5.2. Dopamine Receptors Are Regulated by Oxidative Stress

Oxidative stress, one of the fundamental contributors to the pathogenesis of hypertension, occurs when ROS exceeds the capacity of antioxidant defense systems [114]. Excessive levels of ROS disturb the equilibrium between ROS and antioxidants, leading to the dysfunction of some organs and promoting the development of hypertension [115]. Among the organs regulating blood pressure, the kidney has gained attention as an important organ affected by oxidative stress [116,117].
In rat RPT cells, hydrogen peroxide, an oxidant, increases the levels of malondialdehyde, a marker of oxidative damage, which is accompanied by serine- enhanced phosphorylation of D1R, reduced membranous D1R expression, and its inhibition of NKA activity [118]. This is reflected in in vivo studies. L-buthionine sulfoximine increases oxidative stress, which increases D1R phosphorylation and defective D1R-G protein coupling, impairing D1R-mediated natriuretic response that subsequently leads to hypertension. Treatment with tempol, a superoxide scavenger, decreases oxidative stress, restores D1R-regulated renal function, and normalizes blood pressure [47]. The inhibition of nuclear factor erythroid 2-related factor 2 aggravates oxidative stress and inflammation, impairs renal D1R-induced natriuresis, which contributes to the development of hypertension in mice [119]. These indicate that normalization of renal D1R-mediated natriuretic function by reduction of oxidative stress may be a potential target in the treatment of hypertension.
Renal oxidative stress decreases renal D1R expression and/or increases D1R phosphorylation levels, impairs D1R-mediated natriuresis and diuresis, and increases blood pressure in several hypertensive animal models, including age-associated hypertension, hyperinsulinemia-mediated hypertension, and hypertension in offspring induced by maternal exposures to adverse agents or conditions, such as lipopolysaccharides, fine particulate matters, and maternal diabetes mellitus [112,120]. The detrimental role of oxidative stress in the regulation of D1R expression and its-mediated function has been verified by administration of antioxidants. The inhibition of ROS production by tempol decreases oxidative stress and normalizes blood pressure, accompanied by an increase in the low renal D1R expression and a decrease in hyperphosphorylated D1R [112,120].
Lifestyle is implicated in the development of hypertension [121]. Exercise, as a fundamental factor of lifestyle intervention, exerts many beneficial physiological effects in the regulation of blood pressure [122]. In animals with age-related hypertension, treadmill exercise decreases oxidative stress, restores renal D1R levels in RPT membranes, increases D1R-G protein coupling, and leads to increased sodium excretion [123]. However, another study found that although exercise reduces renal oxidative stress, it does not alleviate impaired renal D1R dysfunction and decrease the high blood pressure in obese Zucker rats, another hypertensive animal model [124]. These studies suggest that the role of oxidative stress in the regulation of D1R function may be different among different hypertensive animal models.

5.3. Regulation of Dopamine Receptor Trafficking

Sorting nexins (SNXs) are a diverse group of proteins orchestrating the trafficking of cargo in the cytoplasm and plasma membrane [125,126]. Our previous studies have shown that deficiency of SNXs disturbs the sorting and trafficking of dopamine receptors, impairs receptor-mediated functions, and increases blood pressure [127].
SNXs play a vital role in the trafficking and signaling of renal D1R. SNX5 colocalizes and dynamically interacts with D1R in the human kidney and RPT cells. SNX5 depletion inhibits agonist-induced D1R endocytosis and cAMP production, and delays D1R recycling. SNX5 also interacts with GRK4, which restrains GRK4 from targeting the phosphorylation of D1R [127]. Renal SNX5 silencing in SHRs results in a further increase in blood pressure, which is accompanied by a decrease in sodium excretion [127]. Another SNX, SNX19, is also involved in the regulation of renal D1R. SNX19, which contains caveolin-1 and flotillin-1 binding motifs, plays an important role in the localization and trafficking of the D1R to lipid raft microdomains [128]. Renal Snx19 silencing decreased renal D1R expression and increased the systolic blood pressure of C57BL/6J mice [128].
The D5R is also regulated by another SNX subtype, i.e., SNX1. Renal SNX1 interacts with D5R and is required for its trafficking. SNX1 depletion in human RPT cells abrogates renal D5R-induced cAMP production and inhibition of sodium transporter activity [129]. The SNX1 and D5R interaction in vitro is reflected in animal studies. Renal-selective SNX1 silencing in C57BL/6J and BALB/cJ mice increases blood pressure and blunts D5R-mediated natriuretic response [129]. Renal SNX1 depletion also increases renal AT1R expression, which is involved in the dysfunction of D5R [69,129]. Snx1 knockout mice have increased blood pressure, accompanied by increased renal ROS production and impaired D5R function, which can be reversed by treatment with antioxidants [130]. In addition, some SNPs of the SNX1 gene are associated with a decrease in systolic blood pressure in response to the diuretic hydrochlorothiazide in hypertensive African-Americans [130]. These studies suggest that the disturbed regulation of SNXs in the trafficking of renal dopamine receptors leads to impaired receptor-mediated sodium excretion and causes hypertension. Trafficking proteins, such as SNX, may be a potential target for the treatment of hypertension.

6. Conclusions and Perspectives

In summary, increasing evidence shows that dopamine receptors play important roles in the regulation of sodium balance and blood pressure. All five dopamine receptor subtypes are expressed in the kidney with distinct distributions in the nephron. Dopamine receptors inhibit the activities and/or expression of renal tubular sodium channels, exchangers, transporters, and pumps, decrease oxidative stress, and interact with other GPCRs. Among the above mechanisms, dopamine receptor-mediated inhibition of renal tubular sodium channels may be the primary mechanism, while the dopamine receptor-mediated regulation of oxidative stress and interaction with other receptors may be secondary. It should be noted that oxidative stress also impairs the expression and function of dopamine receptors. Thus, antioxidants could restore the impaired receptor expression and function in hypertension.
Knockout of any of the five dopamine receptor subtypes may decrease sodium excretion and increase blood pressure. These reports demonstrate that aberrant expression and/or dysfunction of any of the dopamine receptors in the kidney may play an important role in the pathogenesis of hypertension. Thus, further studies targeting specific dopamine receptor subtypes or related regulatory factors may provide new therapeutic antihypertensive strategies in the future.
However, it should be noted that current studies that demonstrate the possible role of renal dopamine receptors in the regulation of blood pressure are mostly based on animal studies and in vitro experiments. There are few human studies in this field, which have only focused on the relationship between SNPs of dopamine receptors and hypertension. Results from animal studies cannot establish a causal relationship in humans. Therefore, more clinical evidence is needed in the future to support the role of renal dopamine receptors in the regulation of blood pressure.

Author Contributions

Conceptualization, J.Y. and P.A.J.; Writing—original draft preparation, J.Y.; Writing—review and editing, J.Y. and P.A.J.; Visualization, J.Y.; Funding acquisition, J.Y. and P.A.J. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported in part by grants from National Natural Science Foundation of China (82370435,82070442), Project of Chongqing Medical Talent Studio (2022), Natural Science Foundation Project of Chongqing (CSTB2023NSCQ-MSX0313), Key Program of The Third Affiliated Hospital of Chongqing Medical University (KY22037), and the National Institutes of Health (P01HL074940, R01DK039308, R01DK119652, and R01DK134574).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing is not applicable to this article because no data were generated or analyzed during this study.

Conflicts of Interest

Dr. Jose, who is the Scientific Director of Hypogen, Inc., is a co-owner of US Patent Number 6660474B1 for GRK4. The other authors report no conflicts.

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Biomolecules 16 00532 g001
Figure 1. The proposed mechanisms by which dopamine receptor subtypes regulate renal function.
Figure 1. The proposed mechanisms by which dopamine receptor subtypes regulate renal function.
Biomolecules 16 00532 g001
Table 1. Summary of renal dopamine receptors-mediated physiological effects and their abnormities in hypertension.
Table 1. Summary of renal dopamine receptors-mediated physiological effects and their abnormities in hypertension.
Receptor
Subtype		Distribution in the KidneyPhysiological Effects in the
Kidney		Aberrant Expression and/or Function
in Hypertension
D1R
(DRD1)		Renal proximal tubule, thick ascending limb of Henle, distal convoluted tubule, cortical collecting ductInhibits renal sodium transport and increases sodium and water excretion [30,31,32,33,34,35]; reduces renal oxidative stress by increasing PON2 expression and inhibiting NADPH oxidase activity [36]; interacts with other systems and receptors in the kidney [37,38]Impaired D1-like receptor-mediated natriuretic and diuretic effects in hypertensive animal models [39,40,41]; impaired D1-like receptor-mediated inhibition of renal proximal sodium transport in human hypertensive subjects [42]; increased D1R serine phosphorylation and subsequent uncoupling of the D1R from its G protein/effector complex [43,44]; decreased renal D1R expression and aberrant interaction between D1R and other receptors in hypertension [37,38,45,46,47]
D2R
(DRD2)		Renal proximal tubule, distal convoluted tubule, cortical and medullary collecting ductsSynergistically interacts with D1R to inhibit renal sodium transport [48] and increases sodium excretion [49]; decreases renal ROS production [50]; increases the synthesis of dopamine in the kidney [51]Decreased plasma membrane D2R expression in urine-derived RPT cells isolated from subjects with inverse salt sensitivity [52]; impaired renal D1-like and D2-like receptor interaction in SHRs [53]
D3R
(DRD3)		Renal proximal tubule, thick ascending limb of Henle, distal convoluted tubule, cortical and medullary collecting ductsInteracts with other GPCRs, e.g., AT1R [54], and D5R [55] and inhibits the expression and/or activities of renal sodium exchangers [56,57]; increases sodium excretion in WKY rats [58], salt-resistant Dahl rats fed normal or high-sodium diet and salt-sensitive Dahl rats fed normal-sodium diet [59]; regulates renal hemodynamics [60]Decreased D3R expression in the renal cortex [61] and RPT cells [54] of SHRs, relative to WKY rats; impaired D3R agonist-induced increased D3R expression in RPT cells of SHRs [54]; impaired D3R-mediated natriuresis in SHRs [58]; aberrant interaction between D3R and other receptors in SHRs [54,55]
D4R
(DRD4)		Renal proximal tubule, distal convoluted tubule, cortical and medullary collecting ductsIncreases sodium excretion and urine volume in Ang II-pretreated WKY rats [62]; inhibits vasopressin-dependent sodium transport and water permeability in the cortical collecting duct [63]; inhibits NKA activity in RPT cells [62]; interacts with other GPCRs, e.g., AT1R [62,64], insulin receptor [65] in the kidney Increased D4R expression in the renal cortex of SHRs [61]; increased phosphorylation of D4R in SHR RPT cells [62]; impaired D4R-induced diuretic and natriuretic effects in SHRs [64]; aberrant interaction between D4R and other receptors in SHRs [62,64,65]
D5R
(DRD5)		Renal proximal tubule, thick ascending limb of Henle, distal convoluted tubule, and cortical collecting ductInhibits renal sodium transport [32,55] and increases sodium and water excretion [66,67]; decreases renal oxidative stress by inhibiting NADPH oxidase [68]; interacts with other systems and receptors in the kidney [69]Decreased D5R expression in SHR RPT cells and renal brush border membranes of SHRs [69]; male hD5RF173L transgenic mice have increased blood pressure, decreased natriuresis and diuresis [67]; decreased Trx1 expression but increased NADPH oxidase activity, ROS generation, and AT1R expression in male hD5RF173L mice [67]
Table 2. Effects of dopamine receptor modification on renal function and blood pressure.
Table 2. Effects of dopamine receptor modification on renal function and blood pressure.
Receptor SubtypeReceptor ModificationAnimal Blood Pressure PhenotypeReceptor-Mediated Functions
D1RSelective renal inhibition of D1R with AS-ODNSystolic blood pressure is not affected by the renal infusion of AS-ODN Drd1 in female SD rats fed normal or high salt diet [33]Reduced urinary sodium and water excretion in AS-ODN Drd1-treated female SD rats fed normal or high salt diet [33]
Global Drd1 knockout miceIncreased systolic and diastolic blood pressures in Drd1 knockout mice fed normal salt diet [34]Impaired dopamine-mediated stimulation of cAMP production in homozygous Drd1 knockout mice [34]
D2RHomozygous global Drd2 knockout mice Increased systolic and diastolic blood pressures [79]; caused salt-dependent increase in blood pressure in male Drd2 knockout mice [80]Increased epinephrine excretion, sympathetic and ETB receptor activities, basal NKA activity in renal cortex and medulla, and urine flow and sodium excretion in Drd2 knockout mice on normal-salt diet [79] but decreased sodium excretion on high-salt diet [80]
Renal cortical Drd2 depletion with siRNAIncreased systolic blood pressure [81]Increased renal inflammation and injury [81]
D3RGlobal Drd3 knockout miceRenin-dependent hypertension [87]; increased systolic and diastolic blood pressure on a normal salt diet [56]Increased renal renin levels [87] and renal AT1R [54] and NHE3 [56] expressions; decreased urinary sodium excretion [54,87]
Global Drd3 knockout miceBlood pressure not increased in male Drd3 knockout mice, regardless of salt intake [88]Decreased urinary sodium excretion on high-salt diet [88]
D4RGlobal Drd4 knockout miceIncreased systolic, diastolic, and mean blood pressures in both male and female Drd4 knockout mice [95]; increased MAP on low, normal, and high salt diet, decreased sodium excretion and right-shifted pressure-natriuresis curve in male Drd4 knockout mice [96]Increased AT1R expression in renal homogenates and membranes [95]; increased expressions of NHE3, NKCC2, and NCC in the kidney, and increased expression of α-ENaC in the renal outer medulla on normal-salt diet; decreased expressions of renal NKCC2, NCC, α-ENaC, and α-NKA on low-salt diet; increased α-ENaC on high salt diet; increased NKCC2, NCC, α-ENaC, and α-NKA in renal plasma membrane on high salt diet [96]
Renal cortical Drd4 depletion with siRNAIncreased systolic blood pressure in male mice fed normal salt diet [97]Increased renal NCC expression but unchanged urinary sodium excretion [97]
D5RGlobal Drd5 knockout miceIncreased systolic, diastolic, and mean blood pressures in mice fed normal sodium diet [68,69,102], and aggravated by a high sodium diet [68,102]increased AT1R expression in the kidney of mice fed normal sodium diet [69,102]; increased expressions of NKCC2, NCC, and α and γ ENaC in the kidney of mice on normal and high sodium diet [102]; increased expressions of NHE3 and NaPi2 in the kidney of mice on high sodium diet [102]; increased renal NADPH oxidase protein expression and activity in the kidney of mice on normal sodium diet that is not affected by a high sodium diet [68]
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Yang, J., & Jose, P. A. (2026). Role of Renal Dopamine Receptors in the Regulation of Blood Pressure. Biomolecules, 16(4), 532. https://doi.org/10.3390/biom16040532

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