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

Roles of Renal Proximal Tubule Transport in the Pathogenesis of Hypertension

Shoko Horita, George Seki*, Hideomi Yamada, Masashi Suzuki, Kazuhiko Koike and Toshiro Fujita
Department of Internal Medicine, Faculty of Medicine, University 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, the kidney plays an essential role in the regulation of blood pressure, but is also quite vulnerable to hypertensive tissue damage. For example, most chronic kidney disease (CKD) patients have hypertension and are revealed to have higher mortality 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, AT1A, dopamine, D1, hypertension, NBCe1, renal proximal tubule, SHR. INTRODUCTION Hypertension has been, and will be, one of the big threats against our health [1, 2]. Many studies show that hypertension raises mortality and morbidity of serious diseases like coronary events and cerebrovascular disorders [1, 3]. Although there are several classes of drugs that are effective for the treatment of hypertension, the etiology of hypertension has not been fully established. According to a lot of studies based on different approaches, a variety of organs and 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 been claimed, which insists the importance of renal factors as the cause of heart disease [6]. Traditionally, the effects of aldosterone on distal nephrons in the pathogenesis of hypertension have been intensively investigated. Recently, however, several hormones acting on renal proximal tubules such as angiotensin II, dopamine, and insulin have been also investigated in relation to the regulation of blood pressure [7-9]. Most of the human mutations resulting in the alterations in blood pressure affect sodium transporters in distal nephrons [10]. Alterations in renal proximal tubule transport may be also linked to the onset of hypertension as well, but the mechanism is not fully clarified [11, 12]. However, there are several evidences that angiotensin II and dopamine are important regulators of blood pressure acting on the proximal tubule [13, 14]. This mini review will discuss the importance of renal proximal tubule for the regulation of blood pressure, and the importance of angiotensin II and dopamine in this aspect. BIPHASIC REGULATION OF RENAL PROXIMAL TUBULE TRANSPORT BY ANGIOTENSIN II Angiotensin II (Ang II) receptors can be divided into two major subtypes, type 1 (AT1) and type 2 (AT2). Type 1 receptor has furthermore two subtypes, AT1A and AT1B in rodents [15, 16]. So far AT1A is shown to be far more abundant than AT1B in the kidney [17-20]. In human only one AT1 receptor has been found [21, 22]. Although AT1 is the main receptor that determines blood pressure, AT2 may be also involved in the regulation of blood pressure [23]. AT2 is abundant in the developing fetus kidney but declines soon after birth [24, 25]. Ang II seems to be directly secreted into proximal tubular lumen by the epithelial cells after the conversion from angiotensinogen [26]. In hypertensive status, angiotensinogen expression is increased and the exaggerated Ang II secretion into the proximal lumen may traverse through the distal nephron and provide substrate for further production of Ang II [27, 28]. Ang II has direct effects on renal tubular functions besides on renal hemodynamics. One of its important effects is on proximal tubule transport, which is considered to have quite an important role in the regulation of whole-body fluid and salt balance [8, 29-31]. It is well known that the concentration 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 interstitial fluid [26, 32, 33]. The Ang II concentration in the proximal tubule is reported to be even higher (30 to 40 nmol/L) [34]. The similar concentration is found in tubular fluid collected from the downstream of proximal tubule [35]. Furthermore it is known that the regulation of circulating Ang II concentration can be dissociated from that of intratubular Ang II concentration [35, 36].

*Address correspondence to this author at the Department of Internal Medicine, 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: georgeseki-tky@umin.ac.jp 1875-6506/13 $58.00+.00

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It has been shown that AT1A receptors in the kidneys are important not only for normal blood pressure regulation but also for mediating the hypertensive response to Ang II infusions [37, 38]. Furthermore others have shown that AT1A knockout mice show hypotension and fail to develop hypertension by unilateral renal arterial constriction [39, 40]. These studies show the critical importance of renal AT1A receptor in the regulation of blood pressure. In the proximal tubule Ang II acts on Na+-HCO3cotransporter (NBCe1), Na+/H+ exchanger 3 (NHE3), and Na+-K+-ATPase in a biphasic way [41-45]. The biphasic effects of Ang II have been reported in proximal tubules from several species. In general, Ang II shows stimulatory effects at picomolar to nanomolar concentrations, and inhibitory effects at nanomolar to micromolar concentrations [8, 29, 46]. Controversial results have been reported as to the receptor subtype(s) mediating the biphasic effects of Ang II [41, 47]. For example, one study reported that AT1 mediates the stimulatory effect, while AT2 mediates the inhibitory effect [48]. However, this study was performed with cultured proximal tubular cells that might express apical AT2. By contrast, using the similar cultured tubular cells the other group reported that AT1 mediates both stimulatory and inhibitory effects [41]. To clarify which receptor is involved in this biphasic effects, we took advantage of AT1A knockout mice [49]. We focused on the effects of Ang II on NBCe1, which mediates a majority of sodium-coupled bicarbonate efflux from the basolateral membranes of proximal tubule [42, 43, 50-54]. In isolated proximal tubules from wild type mice, Ang II showed a stimulatory effect on the NBeC1 activity at a lower concentration (10-10M) but showed an inhibitory effect at a higher concentration (10-6M) [55]. In isolated proximal tubules from AT1A KO mice, the stimulatory effect by the lower Ang II concentration was lost, while the higher Ang II concentration exerted the stimulatory effect. These results indicate that AT1A in the basolateral membrane of wild type proximal tubule is responsible for the biphasic effects of Ang II. They further suggest that AT1B is responsible for the stimulation by the higher concentration of Ang II in the absence of AT1A. Experiments with the specific antagonists of AT1 and AT2 confirmed this hypothesis. In the luminal side, Ang II showed the similar biphasic effects on bicarbonate transport via AT1A in the luminal membrane [56]. To further clarify the signaling pathways underlying the biphasic effects of Ang II, we compared the responses to Ang II in wild type, AT1A KO, and cPLA2 knockout mice. The results revealed that the MEK/ERK signal transduction system mediates the stimulatory effect, while the cPLA2 /P450 pathway is involved in the inhibitory effect [57]. At the same time the activation of cPLA2/P450 pathway seems to suppress the ERK/MEK pathway [58]. These results suggest that the balance between ERK/MEK and cPLA2 /P450 activation via AT1A may determine the final responses of proximal tubular transport to Ang II. This is quite important in view of the extremely high

concentrations of Ang II in the proximal tubular fluid [34]. For example, one study showed that high-salt diet, which suppresses the systemic Ang II concentration as expected, paradoxically raises the Ang II concentration in rat proximal tubule to a level approaching to the inhibitory range [59]. PHYSIOLOGICAL ROLES OF ANG II-MEDIATED REGULATION OF PROXIMAL TUBULE TRANSPORT A series of our studies has clarified that AT1A plays an essential role in the regulation of renal proximal tubule transport, which may have a substantial impact on blood pressure control. On the other hand, Ang II can also regulate blood pressure through the effects on extrarenal tissues including vasculatures. To clarify the relative importance of AT1A in renal and extrarenal tissues in the control of blood pressure, Coffman and colleagues have used a kidney crosstransplantation strategy in AT1A KO and wild type mice to separate the actions of AT1A in the kidney from those in systemic tissues. They demonstrated that distinct and virtually equivalent contributions of AT1A actions in the kidney and in extrarenal tissues to determining the base-line level of blood pressure [60]. They further showed that renal AT1A is absolutely required for the development of Ang IIinduced hypertension and cardiac hypertrophy [38]. To further distinguish the AT1A actions in proximal tubules and other tissues within the kidney, they [61] have made mice lacking AT1A only in the proximal receptors by crossing mice with a conditional Agtr1a allele with a PepckCre transgenic mouse line expressing Cre in proximal but not distal nephron segments [62]. These mice showed approximately 10 mmHg lower blood pressure than that of wild type mice. The transgenic mice also showed significantly lower rates of in vivo proximal fluid reabsorption and GFRs. Furthermore, the transgenic mice showed lower blood pressure elevation (23 +/- 3mmHg) compared to that of wild type mice (38 +/- 5 mmHg) in response to the Ang II infusion. The expression levels of proximal sodium transporters, such as NHE3 and NaPi2 were suppressed after the Ang II infusion in the transgenic mice but not, or suppressed less, in the wild type mice. On the other hand, there were no significant changes in the expression level of NKCC2 and ENaC in Henle loop and distal tubule after Ang II infusion. This study shows that AT1A in renal proximal tubules, by regulating fluid absorption from this segment, plays quite an important role in the regulation of blood pressure. Using androgen-dependent promoter construct, Li et al. made transgenic mice with either overexpression of a constitutively active AT1A transgene or depletion of endogenous AT1A, both specific to the proximal tubule [63]. They demonstrated that the AT1A depleted mice have reduced blood pressure, while the AT1A activated mice showed hypertension in baseline. These results are also consistent with a view that Ang II signaling via AT1A in the proximal tubule regulates systemic blood pressure under baseline conditions.

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Recently proteomic analysis was performed to clarify the Ang 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 of Ang II. At pressor dose 14 proteins among 38 studied proteins were phosphorylated, including PKC, PKCII, GSK3 and GSK3. At non-pressor dose only 7 proteins were phophorylated, including PKC, PKC and GSK. Unexpectedly, phosphorylation of MAPK and ERK1/2 were not altered in proximal tubules in vivo at pressor dose. These signal responses were largely blocked by losartan. This result suggests that signaling pathways involving PKC, PKC, GSK3, GSK3, and cAMP-dependent pathways may have an important role in this model of Ang II induced hypertension. In human, as described above, only one AT1 receptor exists. However, as AT1A is expressed predominantly in most organs such as kidney, heart, brain, adrenal gland, and vascular smooth muscle [17], rodent AT1A may correspond to human AT1 . Therefore the results obtained by AT1A knockout mice [61] may also have significant relevance to the pathogenesis of human hypertension. DOPAMINE AND RENAL PROXIMAL TUBULE Dopamine (DA) is another strong regulator of blood pressure, as well as an essential neurotransmitter. Previous studies have shown that dopamine modulates Ang II actions in the kidney, mainly antagonizing Ang II actions [65, 66]. Cheng et al. have showed that DA decreased AT1 expression in the proximal tubule via D1 receptor, suggesting that dopamine may reset the sensitivity of proximal tubule to Ang II [65]. DA receptors are classified into D1-like (D1, D5) and D2like (D2, D2 and D4) subtypes, closely related G protein-coupled receptors (GPCRs) [67-72]. D1-class dopamine receptors (D1 and D5) activate Gs/orf family of G proteins to stimulate cAMP production by adenylate cyclase (AC), while D2-class dopamine receptors (D2, D3 and D4) couple to the Gi/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 cell and is converted to DA by aromatic amino acid decarboxylase (AADC), both exogenous and endogenous DA may exert signalling. When GDP is bound, G is associated with G/ and is inactive. DA binds to D1 receptor and promotes exchange 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 initiate signalling. G protein-coupled receptor kinase (GRK) desensitizes D1 and decreases their ability to initiate the signalling process. D1, not D5, couples to Go [78], while D5, not D1, couples to Gz and G12/13 [79, 80]. Both are also linked to Gq [8184]. D2-like receptors, D2, D3, and D4 couple to G-proteins Gi and Go, inhibit AC and calcium channel activities, and modulate potassium channel activity [14, 85, 86].

All dopamine receptor subtypes are expressed in the renal tubules and renal vasculature, but not distributed equally along the mammalian nephron. In the renal proximal tubule, all dopamine receptor family is present. In the medullary thick ascending limb of Henle D1, D3 and D5 are expressed, while in the cortical thick ascending limb only D3 exists. In the distal convoluted tubule D1 and D3 are localized while the collecting duct expresses all except D2 [76, 85, 87]. DA inhibits sodium transporters at multiple sites along the 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 may also inhibit ENaC and argininie vasopressin-dependent sodium transport and water permeability [112, 113]. On the other hand, DA stimulates NKCC2 in medullary thick ascending limb. Because Na+-K+-ATPase is inhibited however, the overall transport is decreased [114]. However, the microperfusion studies on isolated proximal tubules have not consistently confirmed a direct tubular effect of DA [115, 116]. One study suggested that DA inhibits proximal transport only in the presence of norepinephrine (NE) [117]. They showed that in isolated rabbit proximal tubules DA inhibits proximal tubule volume reabsorption and net sodium reabsorption, only in the presence of NE. We also observed that DA inhibits the renal proximal NBCe1 activity only in the presence of NE. NBCe1 contributes 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 may require NE to inhibit in vivo sodium reabsorption from proximal tubule. Felder and colleagues have clarified that in the spontaneously hypertensive rat (SHR) there is a defect in the coupling mechanism of D1 and its second messenger [118]. They found that decreased ability of D1 agonists to stimulate AC activity in the proximal convoluted tubules of SHR is due to an altered D1 G protein coupling mechanism. Later they found a similar defect in D1 signaling in the human proximal tubular cells obtained from hypertensive subjects [119]. They also suggested that this uncoupling is one of the important causes of hypertension in the SHR and that the similar mechanism may be also involved in the cause of hypertension in human. [118-120] As mentioned above, DA seems to antagonize AngII effect. Harris and colleagues showed that DA reduces AT 1 expression in rat primary proximal tubular cells [65]. This effect is mediated via D1 receptor while D2 did not have inhibitory effect on AT1 expression. Later Jose and colleagues showed, using human proximal tubular cell lines, that D5 mediates AT1 degradation via a ubiquitin-proteasome pathway [66]. They also proved that D5 knockout mice have elevated AT1 expression and these mice showed raised blood pressure which is blocked by AT1 blockade. On the other hand Aperia and colleagues clarified that, D1 and AT1 make complex and function reciprocal to each other [100]. The interaction between D1 and AT1 is

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Fig. (1). DA signaling in renal proximal tubules. G is associated with G/ and is inactive in corporation with GDP. L-DOPA, precursor of DA, enters the cell and is converted to DA by aromatic amino acid decarboxylase (AADC). Both endogenous and exogenous DA can bind to D1 receptor. DA promotes exchange of GDP with GTP on the G subunit, then G dissociates from G/. Released from G/ and coupled with GTP, G stimulates adenylate cyclase (AC), which produces cAMP. cAMP stimulates PKA that may initiate the inhibitory signalling for sodium transporters. G protein-coupled receptor kinase (GRK) desensitizes D1 and decreases their ability to initiate the signalling process.

attenuated in the presence of AII or DA agonist. They also showed later that losartan, an AT1 antagonist, increases D1 activity in HEK cells and rat proximal tubule cells [121]. The proposed relationship between D1 and AT1 is summarized in Fig. (2). DOPAMINE SIGNALING DEFECTS AND HUMAN HYPERTENSION Felder et al. [122] have shown that single nucleotide polymorphisms of a G protein-coupled receptor kinase (GRK4) are related to human essential hypertension through the increase in G protein-coupled receptor kinase (GRK) activity. These polymorphisms cause the serine phosphorylation and uncoupling of the D1 receptor from its G protein/effector enzyme complex in the proximal tubule and in transfected Chinese hamster ovary cells. They also showed that among GRK4 polymorphisms GRK4A142V

has the most drastic effect on D1 receptor. The GRK4A142V transgenic mice had hypertension. There are seven GRKs, subtypes 1 to 7. Among them mainly GRK4 regulates renal proximal D1 [123]. Unlike other subtypes, GRK4 has four splice variants (GRK4, , , and ) in human, five in rats, and one in mice [123-129]. The GRK4 isoform desensitizes D1 and D3 in a cell-specific manner; GRK4 in CHO and human renal proximal tubule cells [122, 126], GRK4 also desensitizes D1 in HEK-293 cells [130, 131] and D3 in human renal proximal tubular cells [132]. On the contrary, GRK4 does not desensitize AT 1 [133] or parathyroid hormone receptor [126, 134]. The GRK4 locus on human chromosome 4p16.3 may be linked to the increase in blood pressure before adult [135] and hypertension in adult [136]. Adolescents with GRK4 65L/142V/A486 haplotype have a greater increase in blood

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Fig. (2). The interaction between AT1 signalling and D1 signalling. AT1 and D1 may make a functional complex. Activation of either AT1 or D1 may, by dissociating the complex, attenuate the expression of the other receptor. On the other hand, the binding of AT1 antagonist may facilitate the DA signalling.

pressure with age than those with wild-type GRK4 haplotype [137]. However there are some reports that GRK4 variants do not induce hypertension [138, 139]. The relation between GRK4 variants and hypertension would need further investigation. ENDOGENOUS DOPAMINE EFFECTS REGULATING BLOOD PRESSURE ON

Proximal convoluted tubules are known to contain the enzyme AADC, that converts L-DOPA to DA [140-142]. Recently Zhang et al. developed a mouse with defective intrarenal dopamine production [143]. They created the mice without AADC, which plays an essential role in the synthesis of dopamine in the proximal tubule. These mice expressed increased nephron sodium transporters, decreased natriuresis and dieresis in response to L-dihydroxyphenylalanine, and decreased medullary COX-2 expression and urinary prostaglandin E2 excretion. These mice developed saltsensitive hypertension and furthermore showed shorter lifespan than wild type mice. This indicates that dysfunction in endogenous intrarenal dopaminergic system will lead to hypertension and raised mortality, suggesting that Ang II and dopamine may have opposite actions in the viewpoint of both blood pressure and lifespan [144]. CONCLUSION Renal proximal tubule is a key site for regulating blood pressure and fluid balance. Among several factors, Ang II and dopamine are especially important in the regulation of proximal tubule transport. Ang II can increase blood pressure mainly through its effects on the kidney. Recent studies have revealed that the biphasic effects of Ang II on renal proximal tubule transport are mediated by AT1A. Furthermore, balance between ERK/MEK and cPLA2/P450 activities may determine the final tubular responses to

Ang II. The effect of dopamine is rather complicated. DA receptors are expressed in the multiple segments of the tubule, while the proximal tubule expresses all subtypes. The uncoupling of D1-G protein in proximal tubules may be related to the occurrence of hypertension in SHR. Recently it is also suggested that the defective regulation of D1 by GRK polymorphisms may be related to the occurrence of hypertension in humans. Future studies will be warranted to further clarify the roles of renal proximal tubule transport in the regulation of blood pressure. CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES
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Received: March 07, 2012

Revised: June 07, 2013

Accepted: June 12, 2013