REVIEW

Dopamine, kidney, and hypertension: studies in dopaminereceptor knockout mice

Xiaoyan Wang & Van Anthony M. Villar &

Ines Armando & Gilbert M. Eisner & Robin A. Felder &

Pedro A. Jose

Received: 21 January 2008 /Revised: 18 April 2008 /Accepted: 7 May 2008 / Published online: 10 July 2008# IPNA 2008

Abstract Dopamine is important in the pathogenesis ofhypertension because of abnormalities in receptor-mediatedregulation of renal sodium transport. Dopamine receptorsare classified into D1-like (D1, D5) and D2-like (D2, D3, D4)subtypes, all of which are expressed in the kidney. Micedeficient in specific dopamine receptors have been gener-ated to provide holistic assessment on the varying physio-logical roles of each receptor subtype. This reviewexamines recent studies on these mutant mouse modelsand evaluates the impact of individual dopamine receptorsubtypes on blood pressure regulation.

Keywords Dopamine receptor . Hypertension .

Knockout mice . Renal function

Introduction

Hypertension, which affects a quarter of all middle-agedadults, is one of the most common risk factors ofcardiovascular disease. High blood pressure is a phenotypeexpressed by several disorders, and results from an aberrantinteraction between genetic and environmental factors.Hypertension occurs because of the increased activity ofpro-hypertensive systems and/or decreased activity of anti-hypertensive systems [1–4], one of which is the dopaminer-gic system [1, 2]. Therefore, a dysfunction in thedopaminergic pathway may be a mechanism in the devel-opment of essential hypertension.

Mammalian dopamine receptors are G protein-coupledreceptors (GPCRs) belonging to the α group of therhodopsin family (Class A, Family A, or Family 1) andinclude five subtypes identified by molecular cloning [5, 6].The D1 and D5 receptor subtypes are known as D1-likereceptors and couple to G proteins Gs and Golf to stimulateadenylyl cyclase activity. The D2, D3, and D4 receptorsubtypes are known as D2-like receptors and couple to GI

and Go to inhibit adenylyl cyclase activity [1, 2]. D1-likereceptors are typically expressed post-synaptically/post-junctionally, whereas D2-like receptors are also expressedpre-synaptically/pre-junctionally. Distinct cells within thesame organ may co-express different receptor subtypes,rendering cell-specific assignment of receptor subtypesdifficult [2, 7–14]. Dopamine receptor agonists and antag-onists have poor selectivity for individual dopaminereceptors and, consequently, hinder investigation of thespecific roles of each dopamine receptor subtype. Tocircumvent this problem, gene-targeted mutant mousemodels lacking one or more dopamine receptor subtypes[8–13, 15–26] have been generated. Studies using thesemouse models have shed light on the specific physiological

Pediatr Nephrol (2008) 23:2131–2146DOI 10.1007/s00467-008-0901-3

X. Wang :V. A. M. Villar : I. Armando : P. A. Jose (*)Department of Pediatrics, Georgetown University Medical Center,Washington, DC, USAe-mail: pjose01@georgetown.edu

G. M. EisnerDepartment of Medicine, Georgetown University Medical Center,Washington, DC, USA

R. A. FelderDepartment of Pathology,University of Virginia Health Sciences Center,Charlottesville, VA, USA

P. A. JoseDepartment of Physiology and Biophysics,Georgetown University Medical Center,Washington, DC, USA

role of each receptor at the cell, organ, and whole animallevel.

The long-term regulation of blood pressure is accom-plished by both renal and non-renal mechanisms [1, 2, 27–31]. Abnormalities in renal epithelial ion transport playimportant roles in the pathogenesis of essential hypertension,especially in salt-sensitive hypertension. In this review, wesummarize the role of the dopamine receptor subtypes in theregulation of blood pressure in humans and rodents.

Renal distribution of the dopamine receptors

D1 receptor

Human D1 receptor mRNA is expressed in cultured humanrenal proximal tubule cells [32]. In the human kidney [33],D1 receptor immunostaining is found in the apical andbasolateral membrane of the proximal and distal convolutedtubules, medullary thick ascending limb of Henle, maculadensa, and cortical collecting duct, but not in the glomer-ulus and juxtaglomerular cell. D1 receptor protein is alsopresent in the large intrarenal arteries in humans [33], butnot in renal veins. Immunoblotting studies have revealedthe presence of several forms of D1 receptors, varying insize from 50 to 210 kDa, in rat and human renal proximaltubules [34], which is in agreement with data obtained inbrain tissue [35].

Rat Radioligand binding studies of the rat have shown thepresence of D1-like receptors in the renal cortex, but not inglomeruli or medulla [36–41]. However, ligands to bothD1-like receptors have similar affinities and, therefore,cannot pharmacologically distinguish the D1 from the D5

receptor. D1 receptor mRNA is expressed in the ratproximal and distal tubule, arteriole, juxtaglomerularapparatus, but not in the glomerulus or medulla [42–44].It is also expressed in cultured renal proximal tubule cellsfrom the rat [45], mouse (unpublished studies), opossum[46], human [32], and pig [47]. D1 receptor immunostain-ing is present in the rat apical and basolateral membrane ofthe proximal and distal convoluted tubules, medullary thickascending limb of Henle, macula densa, and corticalcollecting duct [7, 48]. Most of the D1 receptors in the ratproximal tubules are located in the S3 segment (unpub-lished observations, 2007). The protein expression of D1

receptors in the inner medullary collecting duct has notbeen documented, but dopamine does not stimulate cyclicadenosine monophosphate (cAMP) production in thisnephron segment [49]. The expression of D1 receptors inthe juxtaglomerular cell [7, 44, 48] has been reported in therat, but not in the human or mouse kidney. Consistent withthe results from mRNA studies and adenylyl cyclase

activation in response to D1-like receptor agonist [2], D1

receptor proteins are not expressed in the rat glomerulus.

Mouse The distribution of D1 receptor protein in the renaltubular segments in the mouse ([2], unpublished studies) issimilar to that in the human and rat kidney.

D2 receptor

There are two D2 receptor isoforms, D2short and D2long,which have been suggested to function pre- and post-synaptically, respectively [50]. The D2short receptor isexpressed more in pre- than in post-synaptic junctions[51, 52].

Rat D2long mRNA is expressed in renal tubules andglomeruli [53]. Immunoblotting [54] revealed that D2

receptor protein is expressed in rat kidney cortex at a majorband of 63 kDa and a minor protein band of 95 kDa(probably a D2 receptor dimer). By indirect immunofluores-cence microscopy, D2 receptor immunostaining is found inthe rat renal cortical proximal tubule, collecting duct, and themesangial cell of the glomerulus [54]. The D2 receptor isexpressed in the intercalated—but not in the principal cell—of the medullary collecting duct. D2 receptor protein is alsoexpressed in an opossum proximal tubule cell line, whichalso exhibits distal tubular cell characteristics [55]. There areno reports of renal tubular D2 receptor expression in thehuman and mouse.

D3 receptor

Human There are no published studies on the location ofthe D3 receptor in non-embryonic human kidney.

Rat Radioligand binding of 7-OH-DPAT, a selective D2 andD3 receptor ligand, has been reported in rat cortical tubulesand mesangial cells [56]. D3 receptor mRNA is expressedin the glomeruli, renal cortical and medullary tubular, andintrarenal vascular tissues [53]. In renal proximal tubules,D3 receptor protein is mainly located in the apical andsubapical areas, but not in the basolateral membrane [57].However, results on the expression of the rat D3 receptoralong the nephron and blood vessels have not beenconsistent. Nurnberger et al. [57] found D3 receptor proteinto be limited to the proximal tubule, whereas O’Connell etal. [58] found the receptor protein in the glomerulus, renalblood vessel, renal proximal tubule, the apical membrane ofthe distal convoluted tubule, in the intercalated cell of thecortical collecting duct, and in the macula densa of the ratkidney, but not in juxtaglomerular apparatus. However, D3

2132 Pediatr Nephrol (2008) 23:2131–2146

receptor mRNA and functional D3 receptors have beendescribed in primary cultures of rat juxtaglomerular cells[59]. The discrepancy between the findings in the kidney insitu and juxtaglomerular cells in vitro suggests that theexpression of D3 receptors is conditional (e.g. culture-dependent). Two species of D3 receptor (45 and 90 kDa) areexpressed in rat renal proximal tubule brush bordermembranes [60] and cells [61], as detected by immuno-blotting studies.

Mouse D3 receptor immunostaining is observed at theapical membrane of the S1 segment of the proximalconvoluted tubule. The staining is also found in the maculadensa, cytoplasm of the thick ascending limb of Henle,distal convoluted tubule, and the glomerulus, but not in themedullary collecting duct [62].

D4 receptor

Human D4 receptor mRNA is expressed in the humankidney [63].

Rat D4 receptor mRNA is not expressed in the glomerulusor the loop of Henle [63], but the D4 receptor protein isfound in cultured rat juxtaglomerular cells [59]. Immuno-blotting analysis of the renal cortex has revealed a minorprotein band of 49 kDa and a major protein band of 38 kDa[54]. D4 receptor immunostaining is present in the S1segment of the proximal tubule, the distal convolutedtubule [64], and especially in the cortical and medullarycollecting ducts, where it is more prominent at thebasolateral area than at the luminal areas. D4 receptorstaining is weak in the glomerulus [54].

Mouse There are no reports on the expression of the D4

receptor in the mouse kidney. Our unpublished studiesindicate that the D4 receptor is expressed throughout thenephron, except at the thick ascending limb of Henle(Fig. 1).

D5 receptor

Human D5 receptor protein is expressed in culturedproximal tubule cells from the human kidney [65].

Rat The D5 receptor protein is expressed in the proximaland distal convoluted tubules, and arteriole, but not in thejuxtaglomerular cell, glomerulus, or macula densa [7, 66–68]. The D5 receptor may be expressed preferentially overthe D1 receptor in the thick ascending limb of Henle and thecortical collecting duct, while the D1 receptor is preferen-

tially expressed in the proximal tubule [69, 70]. Immortal-ized rat renal proximal tubule cells express D5 receptors ofmolecular sizes similar to those of the D1 receptor [71, 72].The D5 receptor is also expressed in the opossum kidney,but not in the opossum kidney cell line [46].

Mouse The D5 receptor immunostaining is located in theapical and brush border membrane of mouse renal corticaltubule [72].

Role of the dopamine receptors in renal physiology

The D1-like receptors

Dopamine produced by the renal proximal tubule plays animportant role in the regulation of sodium excretion,especially when there is a surfeit of sodium in the system[1, 2]. The D1-like dopamine receptors, D1R and D5R,account for 50–70% of renal sodium excretion [1, 2] duringmoderate sodium intake. The inhibition of sodium transportexerted by endogenous renal dopamine is due mainly torenal tubular effects [2, 38, 73], in contrast to exogenouslyadministered dopamine and D1-like receptor agonists whichregulate sodium excretion by both hemodynamic andtubular mechanisms [1, 2, 14, 38, 74–76].

As aforementioned, there are no available ligands that candistinguish the D1 from the D5 receptor. However, it is likelythat the natriuretic effect of dopamine is exerted mainly

Renal Dopamine Receptors and Apical Sodium TransportersDCT

(NCC):D1-5

PCT, PST(NHE3, NaPi2):

D1-5

TAL(NKCC2,NHE3):

D1&D5

CNT,CCD(ENaCs):

D1-5

MCD(ENaCs):

D4

Cortex

Medulla

Fig. 1 Distribution of dopamine receptor subtypes (D1–5) and apicalsodium transporters in rat tubules. PCT Proximal convoluted tubule,PST proximal straight tubule, TAL thick ascending limb of Henle’sloop, DCT distal convoluted tubule, CNT cortical connecting tubule,CCD cortical collecting duct, MCD medullar collecting duct, NHE3sodium hydrogen exchanger type 3, NaPi2 sodium phosphatecotransporter type 2, NKCC2 sodium potassium two chloridecotransporter, NCC sodium chloride cotransporter, ENaC epithelialsodium channel

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through the D1 receptor in renal proximal tubule cells sincethe cAMP production caused by dopamine in these cells ismostly due to D1 receptor activity [77]; the inhibition ofrenal ion transport by D1-like receptors is, in part, mediatedby cAMP. Chronic intrarenal cortical infusion of D1 receptorantisense oligodeoxynucleotides, which selectively decreaseD1 receptor protein expression without affecting the D5

receptor expression [78], provides direct evidence of thespecific D1 receptor role in the inhibition of renal sodiumtransport. In this study, the selective renal cortical inhibitionof D1 receptor expression decreased sodium excretion duringa normal or high salt intake.

The stimulation of D1-like receptors decreases sodiumtransport in the proximal tubule by inhibiting the activity ofseveral sodium transporters, including the sodium hydrogenexchanger 3 (NHE3, SLC9A3), sodium phosphate cotrans-porter (NaPi-IIa/SLC34A1 and NaPi-IIc/SLC34A3), and Cl-/HCO3

- exchanger (SLC26A6) at the apical membrane, andelectrogenic Na+/HCO3

- co-transporter (NBCe1A, SLC4A4),and Na+-K+ ATPase at the basolateral membrane [16, 75,79–86]. In the medullary thick ascending limb of Henle, D1-like receptors decrease sodium transport [87] by inhibitingNa+–K+ ATPase activity, although dopamine increasesNKCC2 (SLC12A1) activity in this nephron segment [88].We have suggested that the D1-like receptor stimulation ofNKCC2 may be important in K+ recycling. Eicosanoids (20-hydroxyeicosatetraenoic acid, 20-HETE) may act synergisti-cally with D1-like receptors to inhibit NKCC2 activity. Gprotein-dependent, cAMP/protein kinase A (PKA)-depen-dent, and protein kinase C (PKC)-independent mechanismsare involved in the D1-like receptor inhibition of Na+/Pi2,NHE3, Na/HCO3

- co-transporter and Cl-/HCO3- exchanger

activity, including their translocation out of the brush bordermembranes [82, 89–94]. On the other hand, D1-like receptorsinhibit Na+–K+ ATPase activity via cAMP/PKA, certainPKC isoforms, and 20-HETE that internalizes Na+–K+

ATPase subunits [2, 83, 95–104]. The mechanism of theinhibitory effect of D1-like receptors on Na+–K+ ATPase isnephron-segment specific. Protein kinase A is involved inD1-like receptor-mediated inhibition of sodium transportersin the cortical collecting duct, while PKC is involved in theproximal convoluted tubule, and the eicosanoids areinvolved in all nephron segments [1, 95–98, 100–103,105–107]. D1-like receptors inhibit NHE3 activity via PKAin rat renal proximal tubule cells [91], while PKC may alsobe involved in opossum kidney cells [107]. Interestingly, theability of D1-like receptors to stimulate calcium uptake inrenal proximal tubule cells, via cAMP and PKC, may play arole in the inhibition of NHE3 activity [108].

In addition to the direct inhibition of sodium excretionby the D1-like receptors per se, these receptors interact withthe D2-like receptors to enhance their inhibitory effect. Wehave reported that the increase in sodium excretion induced

by Z-1046, a dopamine receptor agonist with a rank orderpotency D4 ≥ D3 > D2 > D5 > D1, is blocked by either a D1-like or D2-like receptor antagonist [60]. D2-like receptorsmay potentiate the inhibitory effect of D1-like receptors onNa+-Pi co-transport, NHE3, and Na+-K+ ATPase activitiesin renal proximal tubules (see below).

D1 receptor and renal function

The D1 receptor interacts with other systems, such as therenin–angiotensin–aldosterone and the sympathetic nervoussystems, to tightly regulate renal and cardiovascular func-tions. Angiotensin II exerts its effects on angiotensin II type Ireceptors (AT1R) and opposes the effects of dopamineexerted mainly through the D1-like receptors. D1-like andAT1 receptors have contrasting effects on the generation ofsecond messengers, i.e. D1-like receptors stimulate adenylylcyclases, while the AT1 receptor inhibits them. Both D1-likeand AT1 receptors stimulate phospholipase C activity;however, they stimulate different PKC isoforms [1, 2].Activation of AT1 receptors stimulates all renal proximaltubular ion-transporting proteins that are inhibited by the D1-like dopamine receptors [106, 109–111]. Thus, the effect ofthe D1-like receptors on natriuresis is enhanced whenangiotensin II production is decreased or when AT1 receptorsare blocked [112, 113]. The D1-like receptors can alsocounteract the renal vasoconstrictor effect of angiotensin II[114]. Activation of the D1-like receptors decreases AT1

receptor expression and the number of angiotensin II bindingsites in renal proximal tubule cells from normotensiveWistar–Kyoto (WKY) rats [72, 115]. The use of antisenseoligonucleotides against D1 or D5 receptors points to D5R asthe major negative regulator of AT1R expression [65].However, the D1 receptor can also inhibit AT1 receptorfunction by direct physical interaction [116]. In contrast toAT1 receptors, AT2 receptors participate in the natriuresismediated by the D1-like receptors [117].

D5 receptor and renal function

Activation of D1-like receptors induces diuresis andnatriuresis in WKY rats [1, 2, 38, 39, 117]. Due to thelack of selective D1 and D5 receptor ligands, the relativecontribution of D1 and D5 receptors on natriuresis inresponse to D1-like receptor agonist stimulation is notknown. It is presumed that both D1 and D5 receptors areinvolved because both receptors increase cAMP productionand cAMP mediates the D1-like receptor-mediated inhibi-tion of ion transport [77]. However, as aforementioned,cAMP production is increased to a greater extent by the D1

receptor than by the D5 receptor in renal proximal tubulecells [77] and, thus, the D1 receptor, conceivably, mediatesmost of the natriuretic effect of dopamine [78].

2134 Pediatr Nephrol (2008) 23:2131–2146

D2-like receptors and renal function

The D2-like receptor family consists of the D2, D3, and D4

dopamine receptors. These receptors variably regulatesodium transport [1, 2]. The D2-like receptors can modulaterenal function by regulating dopamine transporter activity[118] and renal dopamine production [119]. Bromocriptine, aD2-like receptor agonist with a tenfold greater affinity for D2

over D3 receptors, stimulates Na+–K+ ATPase activity byincreasing its alpha subunit in the plasma membrane [120,121]. Bromocriptine also increases chloride transport in themedullary thick ascending limb of Henle in rat renalproximal tubules [122]. LY171555, a D2-like receptoragonist with a higher affinity to the D2 receptors, stimulatesNa+–K+ ATPase activity in murine fibroblasts heterologouslyexpressing D2Long [123]. Interestingly, dopamine engendersantinatriuresis in sodium-depleted women [124]. Sulpiride, aD2-like receptor antagonist with equal affinity to all D2-likereceptors, impairs the dopamine-mediated natriuresis involume-expanded women [125]. Thus, activation of D2-likereceptors results in an antinatriuresis in conditions of volumedepletion or in a natriuresis in volume-expanded states.Whether this is a direct effect of the D2-like receptors or dueto their interaction with the D1-like receptors remains to bedetermined. D2-like receptors have also been shown topossess vasodilatory effects, presumably by a pre-junctionalinhibition of catecholamine release [2].

D2 receptor and renal function

In the LTK2 cells expressing the D2Long receptor, activationof D2-like receptors decreases cAMP levels, resulting inincreased Na+–K+ ATPase activity [123]. The selectiveagonists for the D2 receptor, bromocriptine, and LY171555inhibit adenylyl cyclase activities. The resulting decrease incAMP production/PKA activation probably mediates thestimulation of Na+–K+ ATPase activity [120, 123]. The D2

receptor can inhibit adenylyl cyclase activity even in theabsence of adenylyl cyclase V [126], the isoform notexpressed in the kidney [127]. D1 receptor-mediatedactivation of PKC could lead to a D2long-mediatedsensitization of adenylyl cyclase VI [128]. In Chinesehamster ovary (CHO) cells heterologously expressingtenfold more D2 receptors than D1 receptors, stimulationof either receptor results in the potentiation of arachidonicacid release compared to those cells expressing eitherreceptor only [129, 130]; arachidonic acid cytochrome P-450 products have been shown to inhibit renal sodiumtransport [83, 98, 131, 132]. This synergism between D1

and D2 receptors in the production of cAMP, phospholipaseC, and arachidonic acid products might explain theobserved D2 receptor-mediated natriuretic effect. The D1

and D2 receptors can heterodimerize [133] and interact with

each other [130, 134] to increase c-fos [135] and inhibitNa+–K+ ATPase activity [136]. It is conceivable that theD2-like receptors stimulate sodium transport under con-ditions of “low” sodium intake and inhibit Na+–K+ ATPaseactivity in renal proximal tubules cells under conditions of“moderate” sodium excess (in concert with D1-like recep-tors) to synergistically increase sodium excretion [124, 125,137–139].

D3 receptor and renal function

The ability of D3 receptors to mediate natriuresis is sup-ported by the decreased ability of D3 receptor-deficient miceto excrete an acute saline load [17] and corroborated byseveral pharmacological studies. The D3 receptor agonists 7-OH-DPAT and PD128907 [140] have been shown todecrease renal sodium transport [141]. Acute intravenousadministration of 7-OH-DPAT in salt-resistant Dahl ratsincreases glomerular filtration rate and sodium and waterexcretion without affecting blood pressure [141]. PD128907,a selective D3 receptor agonist with a 120-fold selectivityover the D2 receptor, infused directly into the renal artery,dose-dependently increases fractional sodium excretion inWKY rats [but not in spontaneously hypertensive rats(SHR)] fed a normal or high salt diet [142]. Quinerolane, aD2-like receptor agonist with 21-fold selectivity for the D3

over the D2 receptor, opens K+ channels, resulting inhyperpolarization and inhibition of Na+–K+ ATPase activity[143]. The renal effects of D3 receptor activation aremediated by actions on post-junctional glomerular andtubular receptors, and pre-synaptic modulation of norepi-nephrine release because renal denervation attenuates theeffects of 7-OH-DPAT [144].

D4 receptor and renal function

The D4 receptor exerts an antagonistic effect on vasopres-sin- and aldosterone-dependent water and sodium reabsorp-tion in the cortical collecting duct [145, 146]. In the rabbitcortical collecting duct, the D4 receptor-mediated decreasein sodium transport is exerted mainly at the basolateralmembrane despite of greater expression of D4 receptors atthe luminal membrane [146].

The distribution of dopamine receptors and apical sodiumtransporters in rat renal tubules is summarized in Fig. 1.

Aberrant dopamine receptor function and hypertension

D1-like receptors and hypertension

The diuretic and natriuretic responses to administration ofD1-like receptor agonists are impaired in rodents with

Pediatr Nephrol (2008) 23:2131–2146 2135

polygenic hypertension (Dahl salt-sensitive rats and SHRs)[1, 2, 38, 75, 147]. The natriuretic effect of parathyroidhormone and cholecystokinin is not impaired in the SHRs,indicating that the impaired D1-like receptor effect isreceptor-specific [60]. More importantly, the natriureticeffect of dopamine synthesized in the kidney is alsoimpaired in rodent polygenic hypertension [38, 60, 147].In human essential hypertensive subjects, the actions of D1-like receptors on renal hemodynamics and distal renaltubule function (see below) are preserved [148, 149], andfor this reason, the overall natriuretic effect of administeredD1 receptor agonists may be similar or even greater thanthat in normotensive subjects, even when the ability of D1-like receptor agonists to inhibit proximal tubular reabsorp-tion is impaired [148].

The ability of D1-like receptors to inhibit NHE3, Cl-/HCO3

- exchanger, Na+/HCO3- cotransporter, and Na+–K+

ATPase activities is decreased in rodent genetic hyperten-sion which is due, in part, to decreased production ofsecond messengers (e.g. cAMP, diacylglycerol, eicosa-noids) in the renal proximal tubule [16, 37, 71, 75, 86,92, 93, 98, 150–153] and the thick ascending limb of Henle[75]. The D1-like receptor-mediated stimulation of cAMPproduction, however, is not impaired in the corticalcollecting duct of SHRs [154].

The impaired ability of D1-like receptors to stimulatecAMP production in renal proximal tubules is receptorspecific, since the ability of parathyroid hormone tostimulate cAMP production or stimulate G proteins is intact[153, 155, 156] and, at least in young SHRs, β-adrenergicfunction is also intact [157]. Increased serine phosphoryla-tion and decreased expression of D1 receptors at the plasmamembrane [71, 158], are responsible for the impairedability of D1-like receptors to stimulate cAMP productionin renal proximal tubules in genetic hypertension. However,the impairment of D1-like receptor function is organspecific because D1-like receptor function in the brainstriatum is intact [37]. The D1-like receptor defect is geneticbecause it co-segregates with high blood pressure andprecedes the onset of hypertension [16, 37, 159, 160].

Deficiency of the expression of D1-like receptors couldbe involved in human essential hypertension. The humanD1 gene locus on chromosome 5 at q35.1 is linked tohuman essential hypertension [161]. Although there are asyet no reports of the association of polymorphisms of thecoding region of the D1 receptor and essential hypertension,a polymorphism, A-48G, in the 5′-untranslated region isassociated with essential hypertension in Japanese [162]—but not in Caucasians [163]. However, the D1 receptor A-48G polymorphism has been reported to be associated withalbuminuria [164].

The D5 receptor gene locus (chromosome 4p15.1–16.1)is also linked to essential hypertension [165]; the human D5

receptor gene has polymorphisms that code for receptorsabnormally coupled to adenylyl cyclase [166]. The role ofthe D5 receptor in hypertension has been difficult todetermine, mostly due to the fact that the D1 and D5

receptors are pharmacologically indistinguishable. As men-tioned above, the lack of selective ligands makes itimpossible to activate or block only the D1 or D5 receptorin vivo. For this reason, genetic approaches to this problemhave been employed by investigators who used genesilencing techniques to inhibit D1 or D5 receptor expressionand generate D1 or D5 receptor-deficient mice [9, 12, 16,22, 23].

D1 receptor mutant mice

D1 receptor knockout (D1-/-) mice were generated bytargeted mutagenesis with 7.0 kb of the 129/Sv-derivedD1 receptor genomic construct in pPNT [16, 22]. Thehomozygous D1-/- mice have no binding sites for D1-likereceptor antagonists, and in response to D1-like receptoragonist stimulation, they do not increase cAMP accumula-tion although their response to parathyroid hormone isintact. Systolic, diastolic, and mean arterial pressures arehigher in both homozygous and heterozygous mice than inwild-type mice. These data indicate that defective D1

receptor/signal transduction results in increased bloodpressure in mice [16]. However, there is no report availableon the renal function or the activity of the renin-angiotensinII–aldosterone system in D1-/- mice. It is also unknownwhether the hypertension of the null mice is salt-dependent.

D5 receptor-deficient mice

D5 receptor deficient (D5-/-) mice were generated byinjecting into C57BL/6 mouse blastocysts 129/SV embry-onic stem cells containing the targeting construct generatedby ligating the neomycin resistance gene in reverseorientation at the unique SfiI site in the second intracellularloop of the D5 receptor. D5-/- mice are viable, developnormally, and have normal expression of the otherdopamine receptors, including the D1 receptor [23, 167].

Congenic D5-/- mice are hypertensive and salt-sensitive.Blood pressure is also increased in D5+/- mice (Table 1,unpublished data). D5-/- mice have a greater epinephrine/norepinephrine ratio and a greater hypotensive response tothe acute administration of an α-adrenergic blocker [23]than their D5+/+ littermates, indicating that increasedsympathetic activity plays a role in the elevated bloodpressure. However, the percentage decrease in systolicblood pressure, after adrenalectomy, is similar in D5-/- andD5+/+ mice, indicating that central nervous system mech-anisms are involved in the hypertension of D5-/- mice [23,168]. In addition, these central nervous system mecha-

2136 Pediatr Nephrol (2008) 23:2131–2146

nisms, AT1 receptors, and the increased production ofreactive oxygen species (ROS) are also involved in thehypertension of D5-/- mice [14, 66, 72, 169]. However,renal renin protein expression and serum aldosterone levelare not altered in D5-/- mice (unpublished data). D5-/- micealso exhibit proteinuria [170].

D2-like receptors and hypertension

Abnormalities of D2-like receptor function have beenreported in hypertension. One of the polymorphisms ofthe D2 receptor, which results in decreased D2 receptorexpression, is associated with hypertension [171, 172].Moreover, transfer of the segment of chromosome 8 con-taining the D2 receptor gene from the normotensive Brown-Norway rat onto an SHR background decreases bloodpressure [173].

The D3 Ser9Gly receptor variant heterologouslyexpressed in CHO cells impairs D3 receptor-mediatedinhibition of cAMP production, although these cell do

possess the ability to decrease prostaglandin E2 (PGE2)production [174]. However, there is no association betweenthe D3 Ser9Gly, or other D3 receptor gene variants withhypertension [175], despite the chromosome locus of theD3 receptor gene (3q13.3) having been linked to humanessential hypertension [176, 177]. Several studies havedemonstrated that D3 receptor deficiency may be importantin the development of salt-sensitive hypertension. Salt-resistant Dahl rats on a high sodium diet and chronicallytreated with a highly selective D3 receptor antagonist haveincreased blood pressure [178]. The natriuretic effect of a D3

agonist is not evident in hypertensive salt-sensitive Dahl rats[178]. The same research group did not find differences inthe natriuretic effect of a D3 agonist between WKY rats andSHRs [179]. In this study, however, the D3 agonist is givensystemically, and activation of D3 receptors outside thekidney may have had compensating role, thereby obscuring adifferential effect on sodium excretion between WKY andSHRs. When the selective D3 receptor agonist, PD128907, isinfused directly into the renal artery in WKY rats and SHRs

Table 1 Phenotypes of dopamine receptor (DR)-deficient mice and renal mechanism(s) involved in the pathogenesis of hypertension

Mousegenotypes

D1R D5R D2R D3R D4R

-/- +/- -/- +/- -/- +/- -/- +/- -/- +/-

Bloodpressureon 0.8%NaCl diet

Increased[16]

Increased[16]

Increased[23,168,169]

Increased#

Increased[24]

Increased[24]

Increased[17]

Increased[17]

Increased[20]

Normal#

Bloodpressure on4–6%NaCl diet

Increased[68,169]

Increased#

Increased#

Increased#

Kidneydeformities

None # None None # None # None #

Creatinineclearance

& # Normal # Normal[184]

Normal # Normal[20]

Ability toexcrete anacute NaClload

Notimpaired#

Notimpaired[24]

Notimpaired#

Impaired[17]]

Notimpaired[17]

NotImpaired#

Notimpaired#

Ability toexcrete achronicNaCl load

Notimpaired#

Notimpaired#

Impaired[186]

Impaired#

Proteinuria Yes [170] No # No # No #Plasma/Kidneyrenin

Normal # Increased[17]

Increased[17]

Normal[20]

Serum /Urinealdosterone

Normal # Increased[184]

Normal[185]

Normal# Normal #

Renal AT1R Increased[72]

Normal # Increased[17]

Increased[20]

Blank cell indicates no report available; &, indicates normal blood urea nitrogen (BUN); #, indicates unpublished

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fed a high salt diet, fractional sodium excretion is dose-dependently increased in WKY rats but not in SHRs [142].The mechanisms causing the impaired D3 receptor functionin the kidney in hypertension are not completely known. Thestimulatory effect of the D3 receptor agonist, PD128907, onD3 receptor expression is no longer evident in renal proximaltubule cells from the SHRs [180]. It is possible thatmechanisms which impair D1 receptor function in SHR alsoimpair D3 receptor—for example, by increased G protein-coupled receptor-related kinase 4 (GRK4) activity [181]—orthat impaired D1 receptor function results in impairedsynergistic interaction between the D1 and D3 receptor. Inaddition, the impaired natriuretic function of the D3 receptorin SHRs may, in part, be related to the aberrant D3 and AT1

receptor interaction in renal proximal tubule cells [180]. D3

receptor stimulation decreases AT1 receptor expression inrenal proximal tubule cells from the WKY rat, while D3

receptor stimulation increases AT1 receptor expression in theSHR [180].

A locus near the D4 receptor gene (11p15.5) has beenlinked to hypertension. The most intensively studied D4

receptor polymorphism is a 48-bp repeat located in exon 3of the D4 receptor gene. This variant codes for a 16-aminoacid sequence located in the third intracellular loop of theD4 receptor protein, a region that appears to interact with Gproteins and influence intracellular levels of cAMP [182].The number of repeats at the D4 site varies from two to ten,but the four and seven repeat lengths are the most commonin Caucasians in whom the long variant of the D4 gene isassociated with increased systolic and diastolic bloodpressures [183].

The effects of D4 agonists and antagonists on cardiovas-cular and renal function in genetically hypertensive rats havenot been reported. The D4 receptor protein is increased in therenal cortex—but not in the inner medulla—of SHRs relativeto WKY rats [54].

D2 receptor mutant mice

The D2 receptor gene deficient (D2-/-) mice were generatedby homologous recombination in embryonic stem cells withdeletion of exon 7 and the 5′ half of exon 8. These regionsencode the majority of the putative third intracellular loop,the last two transmembrane domains, and the carboxyterminus [24]. D2-/- mice have decreased initiation ofmovement but otherwise normal basic motor skills withouttremor, ataxia, or abnormal stance or posture. D2-/- andD2-/+ mice have higher systolic and diastolic bloodpressures than D2 wild-type (D2+/+) mice. The ability ofD2-/- mice to excrete an acute saline load is similar to thatof D2+/+ mice regardless of the elevated blood pressure,indicating that D2-/- mice have a blunted pressure-natriure-sis response. α-Adrenergic blockade decreases blood

pressure to a greater extent in D2-/- mice than in D2+/+mice. Epinephrine excretion is greater in D2-/- mice than inD2+/+ mice, and acute adrenalectomy decreases bloodpressure to a similar level in D2-/- and D2+/+ mice.Endothelin B (ETB) receptor expression is greater in D2-/-mice than in D2+/+ mice, and an ETB receptor blockerdecreases blood pressure in D2-/- mice but not D2+/+ mice.D2-/- mice may be hypertensive because of enhancedvascular reactivity caused by increased sympathetic andETB receptor activities [24] as well as by increased ROSproduction [184]. The D2-/- mice also have increasedproduction of aldosterone, and treatment with a mineralo-corticoid receptor blocker normalizes blood pressure inthese mice [184]. In contrast, D2+/- mice have normalurinary aldosterone levels [185].

In another strain of D2-/- mice, blood pressure is onlyincreased when the animals are fed a high-salt diet, and thiscondition is associated with a decrease in renal aromatic L-amino acid decarboxylase (AADC) activity and renaldopamine production [26]; AADC converts L-DOPA(levodopa), which is taken up by renal brush bordermembranes, to dopamine. Sympathetic activity is notincreased in these D2-/- mice. Basal urine flow and sodiumexcretion are lower in D2-/- mice than in D2+/+ mice.However, administration of dopamine increases urinevolume and sodium excretion in D2-/- mice to levelssimilar to those found in D2+/+ mice [118]. The differencesbetween the two strains of D2-/- mice could be related todifferences in their genetic backgrounds.

D3 receptor mutant mice

D3 receptor gene deficient (D3-/-) mice have been generatedby targeted mutagenesis. The targeting construct has a 7-kb129/sv-derived D3 receptor genomic sequence in theGKNeo cassette in antisense orientation at the SalI site inexon 2 [15]. The locomotor phenotype of D3 mutants doesnot resemble that of D2 mutants. D3-/- mice developnormally, are fertile, and may show a transient locomotorhyperactivity in a novel environment. D3-/- and D3-/+ micehave higher systolic and diastolic blood pressures than theirwild-type littermates, either on a mixed C57BL/6 and B129background [17] or in congenic C57BL/6 background [62].In contrast, Staudacher et al. reported that D3-/- mice in acongenic C57BL/6 background and on a low, normal, orhigh salt intake have normal blood pressure [186]. Thisreport has to be interpreted with caution because C57BL/6mice from Jackson Laboratories develop hypertensionwhen fed a high NaCl diet [187], while those from Taconic[169] do not. The two strains of D3-/- mice, however, havea decreased ability to excrete an acute or a chronic sodiumchloride load [17, 186], which may lead to an expansion ofthe extracellular fluid volume. Thus, disruption of the D3

2138 Pediatr Nephrol (2008) 23:2131–2146

receptor results in sodium retention, but the hypertension isalso related to increased renal renin production. Renal reninactivity and AT1 receptor expression are greater in D3-/-than in wild-type mice, and blockade of AT1 receptorsdecreases systolic blood pressure more effectively in D3-/-mice than in wild-type ones [17]. Urinary aldosterone levelsare not altered in D3-/- mice (unpublished data).

D4 receptor mutant mice

D4 receptor deficient (D4-/-) mice backcrossed to C57BL/6Jmice for more than six generations have increased systolicand diastolic blood pressures that are increased yet furtherwith increased sodium intake [20]. D4-/- mice do not havealtered circulating or renal renin levels [20] althoughjuxtaglomerular cells in culture also express D4 receptors[59]. Serum/urinary aldosterone levels are not differentbetween D4-/- and D4+/+ mice on a normal or increasedsodium chloride diet (unpublished data). The expression ofAT1 receptors is increased in homogenates of kidney andbrain of D4-/- mice relative to that shown by similarhomogenates of D4+/+ mice, but AT1 receptor expression inthe heart is similar in the two strains. However, thehypotensive effect of a bolus intravenous injection oflosartan, an AT1 receptor antagonist, dissipates after 10min in D4+/+ mice, whereas the effect has been found topersist for more than 45 min in D4-/- mice. Thus,hypertension brought about by the absence of the D4

receptor is mediated, in part, by increased AT1 receptorexpression [20]. While on a normal salt diet (unpublisheddata), the heterozygote mutant D1, D2, D3, and D5 receptormice have increased blood pressure, while D4+/- mice havenormal blood pressure.

Some phenotypes related to renal function in dopaminereceptor deficient mice are summarized in Table 1.

Development of renal dopamine

Development of renal dopamine synthesis

Dopamine-mediated natriuresis and renal vascular effectsare less in younger animals than in older ones. An inversecorrelation between urinary dopamine and age has beenreported in adults [188, 189]. The excretion of dopamine ishigher in the pediatric population than in elderly subjects[190]. However, urinary dopamine increases postnatally invery low birth weight infants [191, 192]. In rats, intrarenallevels of dopamine have a tendency to increase between 3and 20 days after birth, but significantly decrease between20 to 80 days after birth [193]. Urinary excretions ofdopamine and its deaminated metabolite 3,4-dihydroxyphe-nylacetic acid (DOPAC) [194], as well as dopamine

formation in kidney slices, are markedly decreased in oldrats, which have been attributed to decreased uptake of L-DOPA by tubular brush-border membranes [194, 195]. Theuptake of L-DOPA is the rate-limiting step in the renalsynthesis of dopamine [194]. The activity of aromaticAADC, the enzyme involved in the renal synthesis ofdopamine, however, increases with age [195]. The activityof AADC is higher in the adult dog kidney than in 10-dayor 2-month-old dogs [196]. In the rat, AADC immunore-activity can be observed in renal tubule cells as early asgestational day 18 and is present in proximal tubules in theouter and inner cortex 5 days after birth. Aromatic L-aminoacid decarboxylase mRNA is present in the entire cortex bythe sixth post-natal day [193].

Development of renal dopamine receptors

In the rat, renal dopamine D1-like and D2-like receptordensities approach adult values by 3 weeks of age [197,198]. Rat renal D1 receptors are present by the 15th day ofgestational age and increase with maturation [199]. RenalD1 receptors are also expressed in fetal sheep [200].However, in the sheep, the renal cortical affinity ormaximum receptor of D1-like receptors, as determined byradioligand binding, does not change with maturation[201].

In rats, renal D2-like receptor binding does not changewithin the first 2 weeks of life but increases after 3 weeks[202]. In contrast, renal D2-like receptor binding decreaseswith age in sheep [201].

Renal effects of dopaminergic agonists

The decreased natriuretic action of dopamine and D1-likereceptor agonists in the young and the aged has beenattributed to a decreased renal generation of cAMP andinhibition of NHE3 and Na+/K+ ATPase activity inresponse to D1-like receptor stimulation [198, 201–208].Even though renal D1-like receptor densities are notdifferent between 3- and 10-week-old rats, there is animpaired ability of the D1-like agonist fenoldopam tostimulate adenylyly cyclase activity in the young [198,203]. The decreased inhibitory effect of D1-like receptorson NHE activity in young rats is caused, in part, by theincreased expression and activity of the G protein subunit Gβ/γ [208].

In neonatal dogs, pigs, and sheep, the intravenous orintrarenal arterial administration of dopamine alone maynot always increase renal blood flow or decrease renalvascular resistance [209–213]. The systemic or intrarenalarterial infusion of dopamine alone, even in low doses, mayresult in a renal vasoconstriction that is more pronounced inthe fetal and neonatal animals [209, 211, 213]. This is due

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to the occupation of renal α adrenergic receptors thatincrease in number in the perinatal dog and sheep. A lowdose of dopamine injected into the renal artery increasesrenal blood flow and decreases renal vascular resistance inadult dogs [214], but not in young puppies [215]. Even inthe presence of α- and β-adrenergic blockade, dopaminedoes not increase renal blood flow in 1- to 2-week-oldpuppies, but it does increase renal blood flow andglomerular filtration rate in older puppies [215]. Similarresults are observed following intravenous dopamineadministration in young piglets [211]. In spite of theabsence of any change in renal blood flow followingintrarenal arterial infusion of dopamine, sodium excretionincreases, but this effect is less evident in the youngerpuppy than in the older one [215]. Dopamine also increasessodium excretion in the fetal sheep without increasing renalblood flow [213, 216]. Thus, in the very young, thenatriuretic effect of dopamine is probably due mainly totubular factors.

The effects of the D2-like receptor agonist are not wellstudied. However, in the developing animal, selective D2-like receptor agonists increase glomerular filtration rate to asimilar extent as that found in younger and older rats [217].In premature infants, in contrast to the findings in adults, apredominantly D2-like receptor antagonist increases urineflow, sodium excretion, and osmolar clearance, suggestingthat D2-like receptor effects may predominate in the humaninfant [218].

Ability to excrete a salt load in human neonates

Pre-term infants have a decreased ability to retain sodium,but both full-term and pre-term infants have a decreasedability to excrete a salt load [219]. In the pediatric age group,a decrease in sodium intake results in an increase in urinarydopamine, while in adults, a high salt intake results in anincrease in urinary dopamine [212, 218]. Low doses ofdopamine, however, can induce a natriuresis in preterminfants, but it is not known if the magnitude of the responseis different from that reported in the adult [220]. Deficits inrenal dopamine function may be responsible for thediminished ability of the aged kidney to excrete a salt load[221]. Whether this is also true in the neonate has not beendetermined.

Overall summary

In summary, dopamine receptors are important players inthe regulation of renal function and blood pressure. Eachdopamine receptor subtype exerts a unique regulatoryfunction and interacts with other GPCRs, especially thoserelated to angiotensin II. All dopamine receptor subtypes

are present in the kidney, showing a distinct distributionalong the nephron. Renal sodium transport is regulated byall subtypes, either directly or indirectly by interaction withother GPCRs, to maintain sodium balance. Deletion of anyof the dopamine receptor subtypes results in elevated bloodpressure and impaired pressure natriuresis in the mutantmice. Abnormalities of dopamine receptors in their genes/proteins or in their regulation of renal function play animportant role in the pathogenesis of hypertension.

Acknowledgment This work is supported in part by grants from theNational Institutes of Health, HL23081, DK39308, HL074940, andHL68686.

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