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AT1 Angiotensin receptors — vascular and renal


epithelial pathways for blood pressure regulation
Daian Chen1 and Thomas M Coffman1,2

Angiotensin type 1 (AT1) receptors are key effector elements of two distinct pharmacological classes: angiotensin type 1
the renin–angiotensin system, mediating virtually all of the (AT1) and type 2 (AT2) receptors based on their differ-
classical physiological actions of angiotensin II. ential affinities for various nonpeptide antagonists. The
Pharmacological blockade of the AT1 receptor effectively AT1 receptor mediates virtually all of the classically
lowers blood pressure in a substantial proportion of patients recognized physiological actions of Ang II eliciting pow-
with hypertension, indicating the pivotal role of these receptors erful regulation of homeostatic cardiovascular functions
in human hypertension. AT1 receptors are expressed in many while contributing to the pathogenesis of cardiovascular
different organ systems where they have myriad cellular and kidney diseases.
actions. However, several lines of evidence have suggested
that direct actions of AT1 receptors in kidney have a major role AT1 receptors are expressed in all of the key organ
in regulation of blood pressure and in the pathogenesis of systems involved in regulating blood pressure including
hypertension. Here we review recent studies suggesting that the kidney, vasculature, immune system, adrenal gland,
renal epithelium and vasculature may be key cellular targets, heart and both central and peripheral nervous system.
where AT1 receptor activation has powerful physiological Furthermore, the AT1 receptor-associated proteins,
impact. We will also examine novel regulatory mechanisms by ATRAP and ARAP1, have been shown to be important
peptides associated with the C-terminus of the AT1 receptor. in determining the density of AT1 receptors on the cell
Addresses surface by interacting with the carboxyl-terminus of the
1
Division of Nephrology, Department of Medicine, Duke University and AT1 receptor and regulating receptor trafficking and
Durham VA Medical Centers, Durham, NC 27710, USA degradation. This review will focus on the AT1 receptor
2
Cardiovascular and Metabolic Disorders Research Program, Duke-
and its associated proteins in the vasculature and kidney
NUS Graduate Medical School, Singapore 169857, Singapore
epithelia, highlighting key findings that enhance under-
Corresponding author: Coffman, Thomas M (tcoffman@duke.edu) standing RAS biology while pointing toward new strate-
gies for preventing and treating hypertension and
Current Opinion in Pharmacology 2015, 21:122–126
cardiovascular diseases.
This review comes from a themed issue on Cardiovascular and renal
Edited by Pernille BL Hansen and Boye L Jensen
AT1 receptors in kidney epithelia in blood
pressure control
For a complete overview see the Issue and the Editorial
The importance of AT1 receptors in the kidney in regu-
Available online 14th February 2015 lating renal sodium handling and blood pressure has been
http://dx.doi.org/10.1016/j.coph.2015.01.006 long recognized. Activation of AT1 receptors in the kid-
1471-4892/# 2015 Elsevier Ltd. All rights reserved. ney leads to renal vasoconstriction and increased sodium
reabsorption [2–4]. Kidney cross-transplantation studies
from our laboratory using wild-type and AT1A receptor-
deficient mice demonstrated a key contribution of AT1
receptors in the kidney to maintaining baseline blood
pressure [5]. In addition, we found that AT1 receptors in
Introduction the kidney are required for the full phenotype of Ang II-
The renin–angiotensin system (RAS) has a central role in dependent hypertension, promoting hypertension by
blood pressure regulation and fluid balance. While the driving renal sodium retention [6]. However, AT1 recep-
RAS is critical for maintaining normal circulatory homeo- tors are expressed by many cell lineages in the kidney
stasis, especially during episodes of sodium deprivation, including epithelial cells across the nephron and renal
abnormal activation can contribute to the development of vasculature. Our cross-transplantation experiments could
hypertension and end-organ damage. Sequential cleavage not distinguish the relative contributions of these indi-
of the substrate angiotensinogen by renin and angioten- vidual cell lineages to blood pressure control.
sin-converting enzyme (ACE) generates the octapeptide
hormone angiotensin II (Ang II), the major physiological- There is an abundant literature demonstrating effects of
ly active peptide of the RAS. Ang II triggers its biological Ang II acting via AT1 receptors to modulate sodium and
effects by stimulating receptors belonging to the large fluid reabsorption along the nephron, particularly in the
family of 7-transmembrane, G protein-coupled receptors proximal tubule [4,7]. As technology has advanced, more
(GPCRs) [1]. These receptors can be further divided into sophisticated tools are available to allow delineation of

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AT1 receptor — pathways for blood pressure regulation Chen and Coffman 123

AT1 receptor functions in specific cell lineages. Cell- hypertension. In this regard, mice lacking ACE in the
specific gene targeting using the Cre–loxP technique, kidney exhibited enhanced natriuresis and resistance to
which allows precise localization and timing of gene L-NAME-induced hypertension [14]. These mice also
deletions or insertions, has proven very useful for such had preserved glomerular filtration rate (GFR) during L-
physiological studies. Accordingly, we and others used NAME, along with reduced abundance of several key
Cre–loxP techniques to generate mice with cell-specific transporter moieties including NHE3, NaPi2, gENaC,
deletion AT1A receptors from epithelia in the proximal and the phosphorylated forms of NKCC2 and NCC.
tubule of the kidney [8,9]. Our studies showed that AT1 Altogether, these studies highlight the importance of
receptors in the proximal tubule play critical roles both in Ang II generation within the kidney, which then acts
basal blood pressure control and in the pathogenesis of on AT1 receptors on renal epithelium and other cell
Ang II-induced hypertension. This is achieved by modu- lineages, to promote the development of hypertension.
lating fluid and solute reabsorption by the proximal
tubule through controlling the abundance of key sodium Vascular AT1 receptors and end-organ
transporters including the Na+/H+ exchanger 3 (NHE3) damage in hypertension
and the Na+-Pi cotransporter (NaPi2) [8–10]. AT1 receptors are broadly expressed on the vasculature,
particularly in vascular smooth muscle cells (VSMCs) but
In addition to these effects in the proximal tubule, recent also in other cell types involved in vascular pathology
studies have also suggested that direct actions of Ang II including endothelium, adventitia, and macrophages.
on AT1 receptors in the collecting duct can affect blood Along with their actions to induce vasoconstriction and
pressure by directly stimulating the activity of the epi- increase peripheral vascular resistance, vascular AT1A
thelial sodium channel (ENaC) [11]. This study indicat- receptors have been implicated in aneurysm formation.
ed that aldosterone and Ang II act coordinately to increase For example, a role for AT1 receptors has been suggested
the number of functionally active channels during low in humans with Marfan’s syndrome and in non-syndromic
sodium feeding. Furthermore, during Ang II-dependent thoracic aortic aneurysms and dissections [15]. Likewise,
hypertension, ENaC becomes overactive and is not ef- Ang II appears to promote development of aortic aneur-
fectively suppressed by inhibition of the aldosterone– ysms in mouse models with hyperlipidemia and hyper-
mineralocorticoid receptor axis, indicating a major role for tension [15–18]. Specifically, Ang II infusion in mice
direct stimulation by Ang II [11]. leads to pronounced aortic dilation and dissections that
are highly restricted to the ascending aorta, and these
The intra-renal RAS: autonomous regulation effects are modified by genetic background and exagger-
of Ang II generation in the kidney ated in the presence of concomitant atherosclerosis
Previous work by the Navar group and others has docu- [18,19]. Aneurysm formation is prevented by the admin-
mented the existence of an intra-renal RAS with inde- istration of the AT1 receptor antagonist, losartan, indicat-
pendent control of Ang II generation compared to the ing a critical role for AT1 receptors in their pathogenesis
circulating system [12]. These studies suggest a feed- [15]. To define the cell lineage mediating these actions,
forward stimulation of Ang II generation during Ang II- Rateri and colleagues performed bone marrow transplants
dependent hypertension, at a time when there is sup- and cell-specific elimination of AT1A receptors from
pression of the circulating RAS. Recent studies by Gon- endothelium and vascular smooth muscle cells [20].
zalez-Villalobos et al. have clearly demonstrated the Using these approaches, they found that only depletion
importance of the intra-renal RAS in this process, utilizing of AT1A receptors from endothelium attenuated the
mice genetically modified such that they are unable to development of aneurysms, indicating that Ang II infu-
produce Ang II in the kidney [13] These studies high- sion promotes aortic aneurysms via stimulation of AT1A
light a fundamental requirement for de novo generation of receptors expressed by endothelium. However, the
Ang II by ACE in the kidney in the development of Ang mechanism of this surprising finding is not clear.
II-dependent hypertension. Specifically, mice without
renal ACE have a significantly blunted hypertensive To define the contribution of AT1A receptors in vascular
response to chronic Ang II infusion, despite marked smooth muscle cells to aortic remodeling during hyperten-
increases in circulating Ang II. This resistance to hyper- sion, Cre/loxP technology was used to generate mice from
tension was accompanied by alterations in key ion trans- VSMC using a Cre transgene expressed in larger conduit
porters such as Na+/K+/2Cl co-transporter (NKCC2), the vessels but not in resistance vessels such as glomerular
thiazide-sensitive sodium chloride co-transporter (NCC), arterioles [21]. Acute and chronic hypertensive responses
ENaC and pendrin, as well as the transporter activating to Ang II were unaffected in these mice, consistent with
kinases SPAK and OSR1 [13], indicating that intra-renal lack of excision of AT1 receptors from resistance vessels.
generation of Ang II controls the activation of key sodium However, vascular oxidative stress was significantly atten-
transporters and this is a key pathway for hypertension uated in mice lacking AT1 receptors in VSMCs, consistent
pathogenesis. This pathway for intra-renal generation of with a role for these receptors to promote generation reac-
Ang II was also shown to be important in another form of tive oxygen species in Ang II-dependent hypertension.

www.sciencedirect.com Current Opinion in Pharmacology 2015, 21:122–126


124 Cardiovascular and renal

Nonetheless, despite the apparent reduction in oxidative cells [31]. The inhibitory effect of ATRAP on Ang II
stress, the extent of aortic medial expansion induced by Ang action has been demonstrated in vivo [31,32]. For exam-
II was not affected in the mice lacking AT1A receptors from ple, in transgenic mice overexpressing ATRAP in all
smooth muscle. Taken together, these studies suggest that tissues, both inflammatory femoral artery remodeling
actions of AT1A receptors in VSMCs are not required for after injury and cardiac hypertrophy after aortic banding
aortic remodeling in Ang II-dependent hypertension were significantly reduced [32]. These models of end-
[20,21]. organ injury are also attenuated by angiotensin receptor
blockers (ARBs) reflecting their dependence on AT1
Along with regulation by circulating vasoconstrictors such receptors. In another transgenic mouse line with broad
as Ang II, stretch-activated alterations in diameter of over-expression of ATRAP, baseline blood pressures
small peripheral arteries and arterioles is another impor- were unaffected. On the other hand, sodium retention
tant mechanism for controlling vascular tone. These so- and the severity of hypertension during chronic Ang II
called ‘myogenic responses’ allow dynamic autoregula- infusion were attenuated. This was associated with sup-
tion of blood flow through immediate adjustments in pressed renal NCC and aENaC activation [33]. Thus,
vessel diameters, providing pressure-sensitive control generalized over-expression of ATRAP appears to atten-
for maintaining blood flow in the presence of fluctuations uate AT1 receptor actions in the kidney in vivo, consistent
in perfusion pressure. A recent study by Schleifenbaum with its capacity to suppress AT1 receptor signaling.
and colleagues identified a major role for AT1 receptors in
myogenic responses in the systemic and renal vasculature. ATRAP loss-of-function models have also been generat-
Furthermore, these actions were ligand-independent, as ed. Oppermann and colleagues found high blood pres-
they could be detected in the absence of angiotensinogen sure, plasma volume expansion, and suppressed plasma
and, thus, did not require the presence of Ang II [22]. renin in ATRAP knockouts, a phenotype consistent with
Furthermore, this study suggested that the transient re- enhanced AT1 receptor activation in the kidney [31].
ceptor potential channel 6 (TRPC6) and several voltage- Ohsawa and colleagues also developed a line of mice with
gated K+ gene family (KCNQ) channel gene families, targeted ablation of the ATRAP gene. While baseline
previously implicated in myogenic responses, did not make blood pressures were unaffected in their ATRAP-defi-
a major contribution to the response. Instead, these effects cient mouse line, these animals also had exaggerations of
seemed to require an XE991-sensitive K+ channel in hypertension and plasma volume expansion with chronic
VSMC [22]. The more proximal signaling pathways Ang II infusion [34]. Expression and activity of the major
mediating this response are not clear, but previous work sodium transporter in the distal tubules, ENaC, was also
characterizing ligand-independent, stretch-activation of significantly enhanced by chronic Ang II infusion in
AT1A receptors in cardiac myocytes linked this pathway ATRAP knockout mice [34]. On the basis of these
to b-arrestin signaling [23]. studies, ATRAP seems to be a negative modulator of
AT1 receptors in the renal tubules and loss of ATRAP
Specific regulation of AT1 receptor signaling results in enhanced renal absorptive function, leading to
by the intra-cellular proteins ATRAP and volume expansion and hypertension.
ARAP1
The physiological actions of AT1 receptors are controlled The other AT1 receptor associated protein, ARAP1 also
by regulatory mechanisms typical of other GPCRs includ- binds to the C terminal domain of the receptor. However,
ing transcription, desensitization and receptor recycling ARAP1 promotes recycling of the AT1 receptor to the cell
[24]. However, recent studies indicate additional control membrane [26] thereby increasing AT1 receptor expres-
by two intra-cellular proteins: AT1 receptor-associated sion, and potentially enhancing AT1 receptor signaling,
protein, ATRAP [25] and ARAP1 [26], which interact actions that are in direct opposition to ATRAP. In this
with the carboxyl-terminal domain of the AT1 receptor. regard, transgenic mice overexpressing of ARAP1 in the
As with other GPCRs, the carboxyl terminus of the AT1 proximal tubule under the control of the KAP promoter
receptor is phosphorylated and plays an important role in developed salt-sensitivity and Ang II dependent hyper-
regulating receptor desensitization and internalization tension, which was accompanied by marked kidney hy-
[27]. pertrophy [35]. Expression of ARAP1 has been detected
in the renal vasculature of mice and humans [36], and its
ATRAP is a relatively small protein, encoding an open expression is suppressed by Ang II infusion. Thus, these
reading frame of 161 amino acids with a predicted mo- two proteins interacting directly with the carboxyl-termi-
lecular mass of 18 kDa. ATRAP promotes the internali- nus of the AT1 receptor have the capacity to provide
zation of the AT1 receptors in cultured VSMC [28,29] and opposing regulation of AT1 receptor activation and its
inhibits Ang II-mediated intracellular signaling [30]. physiological consequences. With more detailed under-
ATRAP is expressed at high levels in the proximal tubule standing of their functions, it is conceivable that these
of the kidney, particularly the brush border, with negligi- pathways might be exploited therapeutically in cardio-
ble expression in the renal vasculature or juxtaglomerular vascular diseases.

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AT1 receptor — pathways for blood pressure regulation Chen and Coffman 125

Conclusion proximal tubule regulate blood pressure. Cell Metab 2011,


13:469-475.
While the main components of the RAS have been under
9. Li H, Weatherford ET, Davis DR, Keen HL, Grobe JL, Daugherty A,
study for decades and the AT1 receptor was cloned more Cassis LA, Allen AM, Sigmund CD: Renal proximal tubule
than 20 years ago, new facets and complexities of physio- angiotensin AT1A receptors regulate blood pressure. Am J
Physiol Regul Integr Comp Physiol 2011, 301:R1067-R1077.
logical functions of the RAS continue to be uncovered.
Application of cell-specific gene targeting to the RAS has 10. Riquier-Brison AD, Leong PK, Pihakaski-Maunsbach K,
McDonough AA: Angiotensin II stimulates trafficking of NHE3,
identified a key roles for AT1 receptors in the proximal NaPi2, and associated proteins into the proximal tubule
tubule and ACE in the renal parenchyma in the develop- microvilli. Am J Physiol Renal Physiol 2010, 298:F177-F186.
ment of hypertension. AT1 receptor pathways also con- 11. Mamenko M, Zaika O, Prieto MC, Jensen VB, Doris PA, Navar LG,
tribute to aortic aneurysm formation and hypertensive  Pochynyuk O: Chronic angiotensin II infusion drives extensive
aldosterone-independent epithelial Na+ channel activation.
vascular injury, although in the latter case, the effects on Hypertension 2013, 62:1111-1122.
remodeling appear to be driven primarily by blood pres- Direct actions of AT1 receptors in the collecting duct play the predominant
role in activating epithelial sodium channels during chronic Ang II infusion,
sure elevation. Moreover, new pathways for regulation of whereas aldosterone has only modest effects in this setting.
the AT1 receptor mediated by peptides interacting with
12. Navar LG, Prieto MC, Satou R, Kobori H: Intrarenal angiotensin II
the C-terminus of the receptor modulate its function. and its contribution to the genesis of chronic hypertension.
Inhibitors of the RAS are widely used and have efficacy in Curr Opin Pharmacol 2011, 11:180-186.
cardiovascular and kidney disease. Emerging knowledge 13. Gonzalez-Villalobos RA, Janjoulia T, Fletcher NK, Giani JF,
of RAS functions should facilitate optimal use of these  Nguyen MT, Riquier-Brison AD, Seth DM, Fuchs S, Eladari D,
Picard N et al.: The absence of intrarenal ACE protects against
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Conflict of interest statement metabolism and the intra-renal RAS to pathogenesis of hypertension.
Nothing declared. 14. Giani JF, Janjulia T, Kamat N, Seth DM, Blackwell WL, Shah KH,
 Shen XZ, Fuchs S, Delpire E, Toblli JE et al.: Renal angiotensin-
converting enzyme is essential for the hypertension induced
Acknowledgements by nitric oxide synthesis inhibition. J Am Soc Nephrol 2014,
The authors’ work in this area has been supported by funds from Edna and 25:2752-2763.
Fred L. Mandel Center for Hypertension and Atherosclerosis Research, Elimination of ACE in the kidney reduces the severity of a different form of
National Institutes of Health grants (HL056122 and P30DK096493), and hypertension, NO-deficiency caused by L-NAME, suggesting that the intra-
American Heart Association Postdoctoral Fellowship (12POST11750024). renal RAS contributes to the development of hypertension of diverse causes.
15. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK,
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www.sciencedirect.com Current Opinion in Pharmacology 2015, 21:122–126


126 Cardiovascular and renal

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