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ScienceDirect 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 the renin–angiotensin system, mediating virtually all of the classical physiological actions of angiotensin II. Pharmacological blockade of the AT1 receptor effectively lowers blood pressure in a substantial proportion of patients with hypertension, indicating the pivotal role of these receptors in human hypertension. AT1 receptors are expressed in many different organ systems where they have myriad cellular actions. However, several lines of evidence have suggested that direct actions of AT1 receptors in kidney have a major role in regulation of blood pressure and in the pathogenesis of hypertension. Here we review recent studies suggesting that renal epithelium and vasculature may be key cellular targets, where AT1 receptor activation has powerful physiological impact. We will also examine novel regulatory mechanisms by peptides associated with the C-terminus of the AT1 receptor. Addresses 1 Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA 2 Cardiovascular and Metabolic Disorders Research Program, DukeNUS Graduate Medical School, Singapore 169857, Singapore Corresponding author: Coffman, Thomas M ([email protected])

Current Opinion in Pharmacology 2015, 21:122–126 This review comes from a themed issue on Cardiovascular and renal Edited by Pernille BL Hansen and Boye L Jensen

http://dx.doi.org/10.1016/j.coph.2015.01.006 1471-4892/# 2015 Elsevier Ltd. All rights reserved.

Introduction The renin–angiotensin system (RAS) has a central role in blood pressure regulation and fluid balance. While the RAS is critical for maintaining normal circulatory homeostasis, especially during episodes of sodium deprivation, abnormal activation can contribute to the development of hypertension and end-organ damage. Sequential cleavage of the substrate angiotensinogen by renin and angiotensin-converting enzyme (ACE) generates the octapeptide hormone angiotensin II (Ang II), the major physiologically active peptide of the RAS. Ang II triggers its biological effects by stimulating receptors belonging to the large family of 7-transmembrane, G protein-coupled receptors (GPCRs) [1]. These receptors can be further divided into Current Opinion in Pharmacology 2015, 21:122–126

two distinct pharmacological classes: angiotensin type 1 (AT1) and type 2 (AT2) receptors based on their differential affinities for various nonpeptide antagonists. The AT1 receptor mediates virtually all of the classically recognized physiological actions of Ang II eliciting powerful regulation of homeostatic cardiovascular functions while contributing to the pathogenesis of cardiovascular and kidney diseases. AT1 receptors are expressed in all of the key organ systems involved in regulating blood pressure including the kidney, vasculature, immune system, adrenal gland, heart and both central and peripheral nervous system. Furthermore, the AT1 receptor-associated proteins, ATRAP and ARAP1, have been shown to be important in determining the density of AT1 receptors on the cell surface by interacting with the carboxyl-terminus of the AT1 receptor and regulating receptor trafficking and degradation. This review will focus on the AT1 receptor and its associated proteins in the vasculature and kidney epithelia, highlighting key findings that enhance understanding RAS biology while pointing toward new strategies for preventing and treating hypertension and cardiovascular diseases.

AT1 receptors in kidney epithelia in blood pressure control The importance of AT1 receptors in the kidney in regulating renal sodium handling and blood pressure has been long recognized. Activation of AT1 receptors in the kidney leads to renal vasoconstriction and increased sodium reabsorption [2–4]. Kidney cross-transplantation studies from our laboratory using wild-type and AT1A receptordeficient 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 the kidney are required for the full phenotype of Ang IIdependent hypertension, promoting hypertension by driving renal sodium retention [6]. However, AT1 receptors are expressed by many cell lineages in the kidney including epithelial cells across the nephron and renal vasculature. Our cross-transplantation experiments could not distinguish the relative contributions of these individual cell lineages to blood pressure control. There is an abundant literature demonstrating effects of Ang II acting via AT1 receptors to modulate sodium and fluid reabsorption along the nephron, particularly in the proximal tubule [4,7]. As technology has advanced, more sophisticated tools are available to allow delineation of www.sciencedirect.com

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

AT1 receptor functions in specific cell lineages. Cellspecific gene targeting using the Cre–loxP technique, which allows precise localization and timing of gene deletions or insertions, has proven very useful for such physiological studies. Accordingly, we and others used Cre–loxP techniques to generate mice with cell-specific deletion AT1A receptors from epithelia in the proximal tubule of the kidney [8,9]. Our studies showed that AT1 receptors in the proximal tubule play critical roles both in basal blood pressure control and in the pathogenesis of Ang II-induced hypertension. This is achieved by modulating fluid and solute reabsorption by the proximal tubule through controlling the abundance of key sodium transporters including the Na+/H+ exchanger 3 (NHE3) and the Na+-Pi cotransporter (NaPi2) [8–10]. In addition to these effects in the proximal tubule, recent studies have also suggested that direct actions of Ang II on AT1 receptors in the collecting duct can affect blood pressure by directly stimulating the activity of the epithelial sodium channel (ENaC) [11]. This study indicated that aldosterone and Ang II act coordinately to increase the number of functionally active channels during low sodium feeding. Furthermore, during Ang II-dependent hypertension, ENaC becomes overactive and is not effectively suppressed by inhibition of the aldosterone– mineralocorticoid receptor axis, indicating a major role for direct stimulation by Ang II [11].

The intra-renal RAS: autonomous regulation of Ang II generation in the kidney Previous work by the Navar group and others has documented the existence of an intra-renal RAS with independent control of Ang II generation compared to the circulating system [12]. These studies suggest a feedforward stimulation of Ang II generation during Ang IIdependent hypertension, at a time when there is suppression of the circulating RAS. Recent studies by Gonzalez-Villalobos et al. have clearly demonstrated the importance of the intra-renal RAS in this process, utilizing mice genetically modified such that they are unable to produce Ang II in the kidney [13] These studies highlight a fundamental requirement for de novo generation of Ang II by ACE in the kidney in the development of Ang II-dependent hypertension. Specifically, mice without renal ACE have a significantly blunted hypertensive response to chronic Ang II infusion, despite marked increases in circulating Ang II. This resistance to hypertension was accompanied by alterations in key ion transporters such as Na+/K+/2Cl co-transporter (NKCC2), the thiazide-sensitive sodium chloride co-transporter (NCC), ENaC and pendrin, as well as the transporter activating kinases SPAK and OSR1 [13], indicating that intra-renal generation of Ang II controls the activation of key sodium transporters and this is a key pathway for hypertension pathogenesis. This pathway for intra-renal generation of Ang II was also shown to be important in another form of www.sciencedirect.com

hypertension. In this regard, mice lacking ACE in the kidney exhibited enhanced natriuresis and resistance to L-NAME-induced hypertension [14]. These mice also had preserved glomerular filtration rate (GFR) during LNAME, along with reduced abundance of several key transporter moieties including NHE3, NaPi2, gENaC, and the phosphorylated forms of NKCC2 and NCC. Altogether, these studies highlight the importance of Ang II generation within the kidney, which then acts on AT1 receptors on renal epithelium and other cell lineages, to promote the development of hypertension.

Vascular AT1 receptors and end-organ damage in hypertension AT1 receptors are broadly expressed on the vasculature, particularly in vascular smooth muscle cells (VSMCs) but also in other cell types involved in vascular pathology including endothelium, adventitia, and macrophages. Along with their actions to induce vasoconstriction and increase peripheral vascular resistance, vascular AT1A receptors have been implicated in aneurysm formation. For example, a role for AT1 receptors has been suggested in humans with Marfan’s syndrome and in non-syndromic thoracic aortic aneurysms and dissections [15]. Likewise, Ang II appears to promote development of aortic aneurysms in mouse models with hyperlipidemia and hypertension [15–18]. Specifically, Ang II infusion in mice leads to pronounced aortic dilation and dissections that are highly restricted to the ascending aorta, and these effects are modified by genetic background and exaggerated in the presence of concomitant atherosclerosis [18,19]. Aneurysm formation is prevented by the administration of the AT1 receptor antagonist, losartan, indicating a critical role for AT1 receptors in their pathogenesis [15]. To define the cell lineage mediating these actions, Rateri and colleagues performed bone marrow transplants and cell-specific elimination of AT1A receptors from endothelium and vascular smooth muscle cells [20]. Using these approaches, they found that only depletion of AT1A receptors from endothelium attenuated the development of aneurysms, indicating that Ang II infusion promotes aortic aneurysms via stimulation of AT1A receptors expressed by endothelium. However, the mechanism of this surprising finding is not clear. To define the contribution of AT1A receptors in vascular smooth muscle cells to aortic remodeling during hypertension, Cre/loxP technology was used to generate mice from VSMC using a Cre transgene expressed in larger conduit vessels but not in resistance vessels such as glomerular arterioles [21]. Acute and chronic hypertensive responses to Ang II were unaffected in these mice, consistent with lack of excision of AT1 receptors from resistance vessels. However, vascular oxidative stress was significantly attenuated in mice lacking AT1 receptors in VSMCs, consistent with a role for these receptors to promote generation reactive oxygen species in Ang II-dependent hypertension. Current Opinion in Pharmacology 2015, 21:122–126

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Nonetheless, despite the apparent reduction in oxidative stress, the extent of aortic medial expansion induced by Ang II was not affected in the mice lacking AT1A receptors from smooth muscle. Taken together, these studies suggest that actions of AT1A receptors in VSMCs are not required for aortic remodeling in Ang II-dependent hypertension [20,21]. Along with regulation by circulating vasoconstrictors such as Ang II, stretch-activated alterations in diameter of small peripheral arteries and arterioles is another important mechanism for controlling vascular tone. These socalled ‘myogenic responses’ allow dynamic autoregulation of blood flow through immediate adjustments in vessel diameters, providing pressure-sensitive control for maintaining blood flow in the presence of fluctuations in perfusion pressure. A recent study by Schleifenbaum and colleagues identified a major role for AT1 receptors in myogenic responses in the systemic and renal vasculature. Furthermore, these actions were ligand-independent, as they could be detected in the absence of angiotensinogen and, thus, did not require the presence of Ang II [22]. Furthermore, this study suggested that the transient receptor potential channel 6 (TRPC6) and several voltagegated K+ gene family (KCNQ) channel gene families, previously implicated in myogenic responses, did not make a major contribution to the response. Instead, these effects seemed to require an XE991-sensitive K+ channel in VSMC [22]. The more proximal signaling pathways mediating this response are not clear, but previous work characterizing ligand-independent, stretch-activation of AT1A receptors in cardiac myocytes linked this pathway to b-arrestin signaling [23].

Specific regulation of AT1 receptor signaling by the intra-cellular proteins ATRAP and ARAP1 The physiological actions of AT1 receptors are controlled by regulatory mechanisms typical of other GPCRs including transcription, desensitization and receptor recycling [24]. However, recent studies indicate additional control by two intra-cellular proteins: AT1 receptor-associated protein, ATRAP [25] and ARAP1 [26], which interact with the carboxyl-terminal domain of the AT1 receptor. As with other GPCRs, the carboxyl terminus of the AT1 receptor is phosphorylated and plays an important role in regulating receptor desensitization and internalization [27]. ATRAP is a relatively small protein, encoding an open reading frame of 161 amino acids with a predicted molecular mass of 18 kDa. ATRAP promotes the internalization of the AT1 receptors in cultured VSMC [28,29] and inhibits Ang II-mediated intracellular signaling [30]. ATRAP is expressed at high levels in the proximal tubule of the kidney, particularly the brush border, with negligible expression in the renal vasculature or juxtaglomerular Current Opinion in Pharmacology 2015, 21:122–126

cells [31]. The inhibitory effect of ATRAP on Ang II action has been demonstrated in vivo [31,32]. For example, in transgenic mice overexpressing ATRAP in all tissues, both inflammatory femoral artery remodeling after injury and cardiac hypertrophy after aortic banding were significantly reduced [32]. These models of endorgan injury are also attenuated by angiotensin receptor blockers (ARBs) reflecting their dependence on AT1 receptors. In another transgenic mouse line with broad over-expression of ATRAP, baseline blood pressures were unaffected. On the other hand, sodium retention and the severity of hypertension during chronic Ang II infusion were attenuated. This was associated with suppressed renal NCC and aENaC activation [33]. Thus, generalized over-expression of ATRAP appears to attenuate AT1 receptor actions in the kidney in vivo, consistent with its capacity to suppress AT1 receptor signaling. ATRAP loss-of-function models have also been generated. Oppermann and colleagues found high blood pressure, plasma volume expansion, and suppressed plasma renin in ATRAP knockouts, a phenotype consistent with enhanced AT1 receptor activation in the kidney [31]. Ohsawa and colleagues also developed a line of mice with targeted ablation of the ATRAP gene. While baseline blood pressures were unaffected in their ATRAP-deficient mouse line, these animals also had exaggerations of hypertension and plasma volume expansion with chronic Ang II infusion [34]. Expression and activity of the major sodium transporter in the distal tubules, ENaC, was also significantly enhanced by chronic Ang II infusion in ATRAP knockout mice [34]. On the basis of these studies, ATRAP seems to be a negative modulator of AT1 receptors in the renal tubules and loss of ATRAP results in enhanced renal absorptive function, leading to volume expansion and hypertension. The other AT1 receptor associated protein, ARAP1 also binds to the C terminal domain of the receptor. However, ARAP1 promotes recycling of the AT1 receptor to the cell membrane [26] thereby increasing AT1 receptor expression, and potentially enhancing AT1 receptor signaling, actions that are in direct opposition to ATRAP. In this regard, transgenic mice overexpressing of ARAP1 in the proximal tubule under the control of the KAP promoter developed salt-sensitivity and Ang II dependent hypertension, which was accompanied by marked kidney hypertrophy [35]. Expression of ARAP1 has been detected in the renal vasculature of mice and humans [36], and its expression is suppressed by Ang II infusion. Thus, these two proteins interacting directly with the carboxyl-terminus of the AT1 receptor have the capacity to provide opposing regulation of AT1 receptor activation and its physiological consequences. With more detailed understanding of their functions, it is conceivable that these pathways might be exploited therapeutically in cardiovascular diseases. www.sciencedirect.com

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proximal tubule regulate blood pressure. Cell Metab 2011, 13:469-475.

Conclusion While the main components of the RAS have been under study for decades and the AT1 receptor was cloned more than 20 years ago, new facets and complexities of physiological functions of the RAS continue to be uncovered. Application of cell-specific gene targeting to the RAS has identified a key roles for AT1 receptors in the proximal tubule and ACE in the renal parenchyma in the development of hypertension. AT1 receptor pathways also contribute to aortic aneurysm formation and hypertensive vascular injury, although in the latter case, the effects on remodeling appear to be driven primarily by blood pressure elevation. Moreover, new pathways for regulation of the AT1 receptor mediated by peptides interacting with the C-terminus of the receptor modulate its function. Inhibitors of the RAS are widely used and have efficacy in cardiovascular and kidney disease. Emerging knowledge of RAS functions should facilitate optimal use of these inhibitors and may suggest other targets to complement their actions.

Conflict of interest statement Nothing declared.

Acknowledgements The authors’ work in this area has been supported by funds from Edna and Fred L. Mandel Center for Hypertension and Atherosclerosis Research, National Institutes of Health grants (HL056122 and P30DK096493), and American Heart Association Postdoctoral Fellowship (12POST11750024).

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AT1 Angiotensin receptors-vascular and renal epithelial pathways for blood pressure regulation.

Angiotensin type 1 (AT1) receptors are key effector elements of the renin-angiotensin system, mediating virtually all of the classical physiological a...
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