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148 Current Hypertension Reviews, 2013, 9, 148-155

Roles of Renal Proximal Tubule Transport in the Pathogenesis ofHypertension

Shoko Horita, George Seki *, Hideomi Yamada, Masashi Suzuki, Kazuhiko Koike and Toshiro Fujita

Department of Internal Medicine, Faculty o f Medicine, Universi ty of Tokyo, Tokyo, Japan

Abstract: Hypertension is a key factor of cardiovascular disease. Many organs and systems including heart, blood vessel,kidney, sympathetic nerve, and endocrine systems are involved in the regulation of blood pressure. In particular, thekidney plays an essential role in the regulation of blood pressure, but is also quite vulnerable to hypertensive tissuedamage. For example, most chronic kidney disease (CKD) patients have hypertension and are revealed to have highermortality than normal population. Furthermore, hypertensive renal sclerosis is emerging as the third main cause of dialysis

patients. This mini review is to summarize the effects of angiotensin II and dopamine on renal proximal tubule transport,which may have important roles in the regulation of blood pressure.

Keywords: Angiotensin II, AT 1A , dopamine, D 1, hypertension, NBCe1, renal proximal tubule, SHR.

INTRODUCTION

Hypertension has been, and will be, one of the big threatsagainst our health [1, 2]. Many studies show that hyper-tension raises mortality and morbidity of serious diseaseslike coronary events and cerebrovascular disorders [1, 3].Although there are several classes of drugs that are effectivefor the treatment of hypertension, the etiology of hyper-tension has not been fully established. According to a lot ofstudies based on different approaches, a variety of organsand systems including heart, blood vessel, and kidney may

be involved in the onset of hypertension [4, 5].

Recently the idea of cardio-renal relationship has beenclaimed, which insists the importance of renal factors as the

cause of heart disease [6]. Traditionally, the effects ofaldosterone on distal nephrons in the pathogenesis ofhypertension have been intensively investigated. Recently,however, several hormones acting on renal proximal tubulessuch as angiotensin II, dopamine, and insulin have been alsoinvestigated in relation to the regulation of blood pressure[7-9]. Most of the human mutations resulting in thealterations in blood pressure affect sodium transporters indistal nephrons [10]. Alterations in renal proximal tubuletransport may be also linked to the onset of hypertension aswell, but the mechanism is not fully clarified [11, 12].However, there are several evidences that angiotensin II anddopamine are important regulators of blood pressure actingon the proximal tubule [13, 14]. This mini review willdiscuss the importance of renal proximal tubule for theregulation of blood pressure, and the importance ofangiotensin II and dopamine in this aspect.

*Address correspondence to this author at the Department of InternalMedicine, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo,Bunkyo, Tokyo 113-8655, Japan; Tel: +81 3 3815 5411 ext: 33004;Fax: +81 3 5800 8806; E-mail: [email protected]

BIPHASIC REGULATION OF RENAL PROXIMAL

TUBULE TRANSPORT BY ANGIOTENSIN IIAngiotensin II (Ang II) receptors can be divided into two

major subtypes, type 1 (AT 1) and type 2 (AT 2). Type 1receptor has furthermore two subtypes, AT 1A and AT 1B inrodents [15, 16]. So far AT 1A is shown to be far moreabundant than AT 1B in the kidney [17-20]. In human onlyone AT 1 receptor has been found [21, 22]. Although AT 1 isthe main receptor that determines blood pressure, AT 2 may

be also involved in the regulation of blood pressure [23].AT 2 is abundant in the developing fetus kidney but declinessoon after birth [24, 25].

Ang II seems to be directly secreted into proximal tubular

lumen by the epithelial cells after the conversion fromangiotensinogen [26]. In hypertensive status, angiotensinogenexpression is increased and the exaggerated Ang II secretioninto the proximal lumen may traverse through the distalnephron and provide substrate for further production of AngII [27, 28].

Ang II has direct effects on renal tubular functions besides on renal hemodynamics. One of its important effectsis on proximal tubule transport, which is considered to havequite an important role in the regulation of whole-body fluidand salt balance [8, 29-31]. It is well known that theconcentration of Ang II in kidney is much higher than in

plasma. For example, the concentration of Ang II is found to

be 5 to 10 nmol/L in rat kidney interstit ial flu id [26, 32, 33].The Ang II concentration in the proximal tubule is reportedto be even higher (30 to 40 nmol/L) [34]. The similarconcentration is found in tubular fluid collected from thedownstream of proximal tubule [35]. Furthermore it isknown that the regulation of circulating Ang II concentrationcan be dissociated from that of intratubular Ang IIconcentration [35, 36].

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150 Current Hypertension Reviews, 2013 , Vol. 9, No. 2 Horita et al.

Recently proteomic analysis was performed to clarify theAng II induced signal response and onset of hypertension.Zhuo et al . [64] studied the signal protein phosphorylation in

proximal tubules of wild type rats after two week infusion ofAng II. At pressor dose 14 proteins among 38 studied

proteins were phosphorylated, including PKC , PKC II,GSK3 and GSK3 . At non-pressor dose only 7 proteinswere phophorylated, including PKC , PKC and GSK .Unexpectedly, phosphorylation of MAPK and ERK1/2 werenot altered in proximal tubules in vivo at pressor dose. Thesesignal responses were largely blocked by losartan. Thisresult suggests that signaling pathways involving PKC ,PKC , GSK3 , GSK3 , and cAMP-dependent pathwaysmay have an important role in this model of Ang II induced hypertension.

In human, as described above, only one AT 1 receptorexists. However, as AT 1A is expressed predominantly in mostorgans such as kidney, heart, brain, adrenal gland, andvascular smooth muscle [17], rodent AT 1A may correspondto human AT 1 . Therefore the results obtained by AT 1A knockout mice [61] may also have significant relevance tothe pathogenesis of human hypertension.

DOPAMINE AND RENAL PROXIMAL TUBULE

Dopamine (DA) is another strong regulator of blood pressure, as well as an essential neurotransmitter. Previousstudies have shown that dopamine modulates Ang II actionsin the kidney, mainly antagonizing Ang II actions [65, 66].Cheng et al . have showed that DA decreased AT 1 expressionin the proximal tubule via D1 receptor, suggesting thatdopamine may reset the sensitivity of proximal tubule toAng II [65].

DA receptors are classified into D 1-like (D 1, D 5) and D 2-

like (D 2, D2 and D 4) subtypes, closely related G protein-coupledreceptors (GPCRs) [67-72]. D 1-class dopamine receptors (D 1 and D 5) activate G s/orf family of G proteins to stimulatecAMP production by adenylate cyclase (AC), while D 2-classdopamine receptors (D 2, D 3 and D 4) couple to the G i/o family of G proteins and induce inhibition of AC [73, 74].

Fig. ( 1 ) shows a simplified scheme of dopamine signaling[74-77]. Because L-DOPA, precursor of DA, enters the celland is converted to DA by aromatic amino acid decarboxylase(AADC), both exogenous and endogenous DA may exertsignalling. When GDP is bound, G is associated with G / and is inactive. DA binds to D 1 receptor and promotesexchange of GDP with GTP on the G subunit, then G

dissociates from G / . G stimulates adenylate cyclase (AC),which produces cAMP. cAMP stimulates PKA and initiatesignalling. G protein-coupled receptor kinase (GRK)desensitizes D 1 and decreases their ability to initiate thesignalling process.

D1, not D 5, couples to Go [78], while D 5, not D 1, couplesto Gz and G 12/13 [79, 80]. Both are also linked to G q [81-84]. D 2-like receptors, D 2, D 3, and D 4 couple to G-proteinsG i and Go, inhibit AC and calcium channel activities, andmodulate potassium channel activity [14, 85, 86].

All dopamine receptor subtypes are expressed in therenal tubules and renal vasculature, but not distributedequally along the mammalian nephron. In the renal proximaltubule, all dopamine receptor family is present. In themedullary thick ascending limb of Henle D 1, D 3 and D 5 areexpressed, while in the cortical thick ascending limb only Dexists. In the distal convoluted tubule D 1 and D 3 are localizedwhile the collecting duct expresses all except D 2 [76, 85, 87].

DA inhibits sodium transporters at multiple sites alongthe renal tubule and acts on multiple targets possibly via D1

NHE1 [88], NHE3 [89-92], Na +-K +-ATPase [93-106], Na/PiIIa [107-110], and possibly NCC [111]. Via D4 it mayalso inhibit ENaC and argininie vasopressin-dependentsodium transport and water permeability [112, 113]. On theother hand, DA stimulates NKCC2 in medullary thickascending limb. Because Na +-K +-ATPase is inhibitedhowever, the overall transport is decreased [114].

However, the microperfusion studies on isolated proximal tubules have not consistently confirmed a directtubular effect of DA [115, 116]. One study suggested that

DA inhibits proximal transport only in the presence ofnorepinephrine (NE) [117]. They showed that in isolatedrabbit proximal tubules DA inhibits proximal tubule volumereabsorption and net sodium reabsorption, only in the

presence of NE. We also observed that D A inhibits the renal proximal NBCe1 activity only in the presence of NE. NBCe1contributes sodium reabsorption in the basolateral side of

proximal tubule, so this means that DA induces natriuresis in proximal tubule [54]. These results suggest that DA mayrequire NE to inhibit in vivo sodium reabsorption from

proximal tubule.

Felder and colleagues have clarified that in thespontaneously hypertensive rat (SHR) there is a defect in thecoupling mechanism of D 1 and its second messenger [118].They found that decreased ability of D 1 agonists to stimulateAC activity in the proximal convoluted tubules of SHR isdue to an altered D 1 G protein coupling mechanism. Laterthey found a similar defect in D 1 signaling in the human

proximal tubular cells obtained from hypertensive subjects[119]. They also suggested that this uncoupling is one of theimportant causes of hypertension in the SHR and that thesimilar mechanism may be also involved in the cause ofhypertension in human. [118-120]

As mentioned above, DA seems to antagonize AngIIeffect. Harris and colleagues showed that DA reduces ATexpression in rat primary proximal tubular cells [65]. Thiseffect is mediated via D1 receptor while D 2 did not haveinhibitory effect on AT 1 expression. Later Jose andcolleagues showed, using human proximal tubular cell lines,that D 5 mediates AT 1 degradation via a ubiquitin-proteasome

pathway [66]. They also proved that D 5 knockout mice haveelevated AT 1 expression and these mice showed raised blood

pressure wh ich is blocked by AT 1 blockade.

On the other hand Aperia and colleagues clarified that,D1 and AT 1 make complex and function reciprocal to eachother [100]. The interaction between D 1 and AT 1 is

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Roles of Renal Proximal Tubule Transport in the Pa thogenesis Current Hypertension Reviews, 2013 , Vol. 9, No. 2 151

attenuated in the presence of AII or DA agonist. Theyalso showed later that losartan, an AT 1 antagonist, increasesD1 activity in HEK cells and rat proximal tubule cells[121]. The proposed relationship between D 1 and AT 1 issummarized in Fig. ( 2).

DOPAMINE SIGNALING DEFECTS AND HUMAN

HYPERTENSIONFelder et al . [122] have shown that single nucleotide

polymorphisms of a G protein-coupled receptor kinase(GRK4 ) are related to human essential hypertensionthrough the increase in G protein-coupled receptor kinase(GRK) activity. These polymorphisms cause the serine

phosphorylation and uncoupling of the D 1 receptor from itsG protein/effector enzyme complex in the proximal tubuleand in transfected Chinese hamster ovary cells. They alsoshowed that among GRK4 polymorphisms GRK4 A142V

has the most drastic effect on D 1 receptor. The GRK4 A142Vtransgenic mice had hypertension.

There are seven GRKs, subtypes 1 to 7. Among themmainly GRK4 regulates renal proximal D 1 [123]. Unlikeother subtypes, GRK4 has four splice variants (GRK4 , ,and ) in human, five in rats, and one in mice [123-129]. The

GRK4 isoform desensitizes D 1 and D 3 in a cell-specificmanner; GRK4 in CHO and human renal proximal tubulecells [122, 126], GRK4 also desensitizes D 1 in HEK-293cells [130, 131] and D 3 in human renal proximal tubular cells[132]. On the contrary, GRK4 does not desensitize AT[133] or parathyroid hormone receptor [126, 134].

The GRK4 locus on human chromosome 4p16.3 may belinked to the increase in blood pressure before adult [135]and hypertension in adult [136]. Adolescents with GRK465L/142V/A486 haplotype have a greater increase in blood

Fig. (1). DA signaling in renal proximal tubules. G is associated with G / and is inactive in corporation with GDP. L-DOPA, precursor ofDA, enters the cell and is converted to DA by aromatic amino acid decarboxylase (AADC). Both endogenous and exogenous DA can bind toD1 receptor. DA promotes exchange of GDP with GTP on the G subunit, then G dissociates from G / . Released from G / and coupledwith GTP, G stimulates adenylate cyclase (AC), which produces cAMP. cAMP stimulates PKA that may initiate the inhibitory signallingfor sodium transporters. G protein-coupled receptor kinase (GRK) desensitizes D 1 and decreases their ability to initiate the signalling process.

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pressure with age than those with wild-type GRK4 haplotype[137]. However there are some reports that GRK4 variantsdo not induce hypertension [138, 139]. The relation betweenGRK4 variants and hypertension would need furtherinvestigation.

ENDOGENOUS DOPAMINE EFFECTS ONREGULATING BLOOD PRESSURE

Proximal convoluted tubules are known to contain theenzyme AADC, that converts L-DOPA to DA [140-142].Recently Zhang et al . developed a mouse with defectiveintrarenal dopamine production [143]. They created the micewithout AADC, which plays an essential role in the synthesisof dopamine in the proximal tubule. These mice expressedincreased nephron sodium transporters, decreased natriuresisand dieresis in response to L-dihydroxyphenylalanine, anddecreased medullary COX-2 expression and urinary

prostaglandin E 2 excretion. These mice developed salt-sensitive hypertension and furthermore showed shorterlifespan than wild type mice. This indicates that dysfunctionin endogenous intrarenal dopaminergic system will lead tohypertension and raised mortality, suggesting that Ang II anddopamine may have opposite actions in the viewpoint of

both blood pressure and lifespan [144].

CONCLUSIONRenal proximal tubule is a key site for regulating blood

pressure and fluid balance. Among several factors, Ang IIand dopamine are especially important in the regulation of

proximal tubule transport . Ang II can increase blood pressure mainly through its effects on the kidney. Recentstudies have revealed that the biphasic effects of Ang II onrenal proximal tubule transport are mediated by AT 1A .Furthermore, balance between ERK/MEK and cPLA2 /P450activities may determine the final tubular responses to

Ang II. The effect of dopamine is rather complicated. DAreceptors are expressed in the multiple segments of thetubule, while the proximal tubule expresses all subtypes. Theuncoupling of D 1-G protein in proximal tubules may berelated to the occurrence of hypertension in SHR. Recentlyit is also suggested that the defective regulation of D 1 byGRK polymorphisms may be related to the occurrence ofhypertension in humans. Future studies will be warranted tofurther clarify the roles of renal proximal tubule transport inthe regulation of blood pressure.

CONFLICT OF INTEREST

The author(s) confirm that this article content has noconflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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Received: March 07, 2012 Revised: June 07, 2013 Accepted: June 12, 2013

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