Published online before print July 19, 2004, doi: 10.1161/01.HYP.0000136645.90116.1a
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(Hypertension. 2004;44:352.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Membrane Trafficking of Angiotensin Receptor Type-1 and Mechanochemical Signal Transduction in Proximal Tubule Cells
From the Department of Physiology and Biophysics Case Western Reserve University, Cleveland, Ohio.
Correspondence to Ulrich Hopfer, Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106-4970. E-mail ulrich.hopfer{at}case.edu
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Abstract |
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Cellular localization and trafficking of the major angiotensin receptor, AT1, was studied in mouse proximal tubule cell lines because angiotensin II concentrations in the luminal fluid of proximal tubules are greater than the Kd of the receptor and would predict high turnover rates of the receptor. Mouse proximal tubule cells can exist in 2 polarized, differentiated states after confluence: a protoepithelium and a highly differentiated epithelium. The latter is distinguished by greater polarization of the microtubule cytoskeleton and collection of apical microtubule-dependent membrane proteins in condensed apical recycling endosomes (CARE) in proximity to the primary cilium. AT1, AT2, and the sodium hydrogen exchanger NHE3 are localized to CARE. With fluid movement, AT1 receptors externalize from CARE to the apical plasma membrane and allow luminal angiotensin II to initiate cell signaling. These data suggest that fluid movement controls receptor externalization and, hence, a model in which ciliary deflection results in transduction of a mechanical stimulus into the chemical signaling of the AT1 receptor.
Key Words: receptors, angiotensin • epithelium • microscopy • kidney
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Introduction |
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Angiotensin II (Ang II) is a key hormone involved in absorption of sodium by proximal tubules.1,2 It acts through the G-protein coupled surface receptors AT1 and AT2 in humans or AT1a, AT1b, and AT2 in rodents. Although much is known about the signaling pathways downstream from the receptors, the physiological mechanisms involved in regulating proximal tubule sodium absorption by Ang II are not fully understood. The proximal tubule contains all elements of a complete renin-angiotensin system (ie, angiotensinogen, renin, angiotensin converting enzyme, and Ang II).3–6 Measured Ang II concentrations in the proximal tubular luminal fluid are 6 to 10 nmol/L,4,6–8 ie, values that are 100 to 1000x the systemic concentration and above the Kd of Ang II receptors.9 These findings are incompatible with classical concepts of hormonal regulation by modulation of hormone (ligand) concentration. For example, only a limited dynamic range is available for regulation if baseline concentrations of the hormone are already above the Kd of the cognate receptor.
High Ang II concentrations predict high internalization rates for AT1 receptors that are on the surface and therewith high turnover rates. Past experiments have shown G-protein coupled receptor internalization as a way to downregulate from a "baseline" state and that in epithelial cells, apical membrane proteins recycle through an intracellular compartment termed "apical recycling endosomes."10 Therefore, membrane trafficking of AT1 was investigated in vitro using mouse proximal tubule (mPT) cell lines. Experimental conditions that promote differentiation of polarized cells similar to that of cells in vivo were used so that any findings would be relevant for understanding behavior of cells in vivo. mPT cell lines were derived from microdissected proximal tubule segments of the Immortomouse (Ludwig Institute for Cancer Research, United Kingdom). This transgenic mouse harbors a temperature-sensitive version of the immortalization gene SV40 large T antigen (ts-SV40-l-Tag) under control of interferon-
response elements. Therefore, the proximal tubule cells from these animals are conditionally immortal and can be expanded at the permissive temperature of 33°C, whereas a switch to the mouse body temperature of 39°C allows a high degree of differentiation under appropriate conditions.11
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Materials and Methods |
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Cell Culture
mPT cell lines were maintained on collagen-coated Millicell-CM culture plate inserts (Millipore Corp) to promote a polarized epithelial phenotype. Two different types of conditions were used: (1) expansion at 33°C until cells formed a confluent and resistive monolayer and (2) differentiation at 39°C. Under expansion conditions, cells were incubated at 33°C with renal tubular epithelial medium12 plus epidermal growth factor, interferon-
, and 5% FBS applied to both apical and basolateral compartments. For greater differentiation, cells were switched after confluence to 39°C in renal tubular epithelial medium with 1 nmol/L L-3,3',5-triiodothyronine, no epidermal growth factor or interferon-, and 5% FBS only on the basal side. To assess the effect of fluid movement on cells, culture plates were placed in the incubator on a rotary shaker at 
1 Hz.
Immunocytochemistry
Fixation and immunocytochemistry were performed using standard techniques. To preserve the microtubule cytoskeleton, prefixation wash and fixation were carried out at 33°C and room temperature, respectively. Details about antibodies and indirect immunofluorescence are provided in an expanded Methods section available in an online supplement at http://www.hypertensionaha.org. Antibody AT1 N10 (Santa Cruz Biotechnology) was used for Figures 2 to 4 
and Figure 6 in this study to detect AT1. Specificity of primary antibodies was established by omission in the immunocytochemical staining protocol and, in the case of peptide-specific antibodies, with blocking peptides in both immunocytochemistry and Western blots (see online supplement).
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Microscopy and Image Analysis
Image stacks were acquired with a Zeiss 200 M inverted microscope with a DG4 fluorescent light source (Sutter Instrument Co) and a 12-bit CoolSnapHQ camera (Roper Scientific) under control of Metamorph v4.5 (Universal Imaging Corp). Images were deconvolved by Autoquant’s Autodeblur (blind deconvolution) software (AutoQuant Imaging, Inc).
Statistical Analysis
Statistical analysis was done by ANOVA and Student paired t test as appropriate.
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Results |
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In Vitro Differentiation States of Polarized Proximal Tubule Cells
The physiological state of cells in culture and therewith the physiological relevance of experimental results depend strongly on culture conditions. Adherent epithelial cells, such as proximal tubule cells, must be grown on permeable supports and form electrically resistive monolayers to be considered minimally differentiated. However, that is not sufficient because Al-Awqati et al have shown that renal intercalated cells in cell culture can exist in a "protoepithelial" and "terminally differentiated epithelial" state with very different electrolyte transport properties, whereby only the latter state has relevance to the in vivo situation.13 For proximal tubule cells in culture, cellular changes that occur with differentiation beyond the protoepithelial state have not been described, but are highly relevant in the context of a study on membrane trafficking because the organization of the cytoskeleton is a major determinant of this process.
mPT cells were grown to confluence at 33°C (protoepithelial state) and then switched to 39°C without added growth factors to allow for differentiation (highly differentiated state). This switch resulted in reorganization of a number of cellular parameters and formation of distinct condensed apical recycling endosomes (CARE) described later. The appearance of this distinct cellular compartment is one reason to consider the cells at 39°C as highly differentiated. mPT cells in vivo have been shown to rapidly move certain apical transporters, such as Na+/H+ exchanger type 3 (NHE3), into a distinct subapical compartment14 from which the transporters can recycle to the surface.
Confluent monolayers of proximal tubule protoepithelia were characterized by tight junctions (specific conductance of 7 mS/cm2), formation of a primary cilium, and active Na+-dependent phosphate as well as succinate absorption from the apical compartment (Philip G. Woost, 2004, unpublished data). Na+-dependent phosphate and succinate transport are typical proximal tubule functions.15 When cells were switched to differentiation conditions, striking changes were observed in microtubule and apical glycoprotein organization, whereas other parameters, such as Na+-dependent succinate transport, remained unchanged.
In protoepithelial monolayers, microtubules form a meshwork below the apical plasma membrane with dense microtubules running parallel to the lateral plasma membrane and few microtubules extending into the perinuclear region (Figure 1A). In highly differentiated monolayers, microtubules form a ring in the apical cytoplasm with radial extensions. Microtubules were highly diminished along the lateral plasma membrane and not detectable at the basal pole of cells, at least relative to the dense ring and web at the apical pole (Figure 1B). These results with proximal tubule cells are in agreement with previous studies in which filter-grown Madin-Darby canine kidney (MDCK) cells exhibited a polarized distribution of microtubules with major concentration in the supranuclear region of the cell at 48 hours after confluence.16,17
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Surface glycoproteins were assessed by binding of wheat germ agglutinin (WGA), a lectin that binds to glycoproteins containing dimers and trimers of N-acetylglucosamine.18 Prominent, relatively uniform WGA staining of microvilli and the apical portion of lateral borders is illustrated for protoepithelial cells in Figure 1C. With differentiation, WGA staining of the brush border becomes even more pronounced. In addition, a new feature appears, namely the development of a distinct apical plasma membrane area devoid of WGA-stainable glycoproteins. This area is located close to the center of the cell in x-y projections and often bordered by a ring of intense staining (Figure 1D). Notably, this unique region within the apical plasma membrane is located above the microtubule ring that forms in the apical pole under the same differentiation conditions.
The development of a primary cilium is an expression of the polarized nature of cells and is closely associated with the organization of the microtubule cytoskeleton. The primary cilium of proximal tubule cells is nonmotile.19 Primary cilia are present in protoepithelial cells where they stain with WGA. Figure 1E illustrates a transitional monolayer with formation of an apical plasma membrane region devoid of glycoproteins, but the presence of WGA-stained cilia. In highly differentiated proximal tubule monolayers, cilia are present with an approximate length of 3 to 5 µm (Figure 1F), but they do not stain with WGA. Therefore, absence of WGA-stainable glycoproteins on the ciliary membrane provides one criterion to assess the differentiation state. The described pattern of changes in microtubule structure and organization of surface glycoproteins was seen in at least 5 of 8 different mPT cell lines. Most of the subsequent studies were carried out with cell line mPT 32101.
Localization of AT1 Is Microtubule Dependent
mPT cells stably and abundantly express AT1 in both protoepithelial and highly differentiated states as judged from Western blots and immunocytochemistry. Antigenic specificity was established by the use of blocking peptides and 3 different antibodies directed against either the N- or C-terminus of AT1 (see the online supplement). The different antibodies gave essentially identical results in immunocytochemical experiments.
In protoepithelia, AT1 is found in vesicles that are dispersed throughout the cell as well as at the apical and basolateral plasma membranes (Figure 2A to 2D). In contrast, in highly differentiated cells, vesicles containing AT1 receptors relocate to the subapical region and give rise to a distinct lobular ring structure (Figure 2E to 2H and online supplement Movie I). This structure resembles condensed apical recycling endosomes in MDCK cells20,21 and is referred to as CARE. A close-up view shows dense staining at the most apical end with extensions and branching that become fainter toward the nucleus. It is likely that AT1 in CARE represents a form of the receptor that is ready to bind ligand because a high proportion of a signal transduction molecule for AT1, namely G
i, is also located in the same structure (Figure 2I). In x-y projections, the location of the center of CARE coincides with that for the microtubules (Figure 3A to 3C) and the area of the plasma membrane devoid of WGA binding (Figure 2G). However, the width of the 3 structures differs, which, for example, is seen as partial overlap of the AT1 ring with the microtubule ring. Nevertheless, the appearance of the 3 structures in close proximity when cells differentiate indicates that they are related and may operate together in a particular cell function. Relocalization of AT1 to the subapical, supranuclear region begins within 60 minutes after cells are exposed to differentiation conditions and remains as such for at least 12 hours.
To test the dependence of AT1 collection in the apical ring structure on an intact microtubule cytoskeleton, differentiated monolayers were either exposed to 10 µmol/L nocodazole or to cold temperature (0°C) for 30 minutes. Both treatments result in disassembly of microtubules. Interestingly, both treatments disassembled the ring structure of AT1 and dispersed AT1-containing vesicles throughout the cell, in addition to the expected destruction of the normal distinct architecture of the microtubule cytoskeleton (Figure 3A to 3F). Colocalization experiments of AT1 with detyrosinated tubulin, which is the specific form of tubulin found in the ciliary axonema, indicate that the ring formed by vesicles containing AT1 is adjacent to the cilium, with minimal overlap (Figure 4A to 4C).
Coupling of Ciliary Stimulation to Externalization of AT1
The microtubule dependence of the movement of AT1-containing vesicles to CARE adjacent to the primary cilium in differentiated cells suggests that the cilium may also play a role in trafficking of AT1 through the cell. Recent studies by Praetorius and Spring22 and Nauli et al23 in MDCK and collecting duct cells, respectively, indicate that the primary cilium of differentiated cells functions as a flow sensor using Ca2+ influx and elevated cytosolic Ca2+ to signal changes to the rest of the cell. However, in cell culture, there is typically little fluid movement across the apical plasma membrane, and Ca2+ influx via the ciliary route is probably low. As elevated cytosolic Ca2+ constitutes a fusion signal in most cells, the accumulation of AT1 in CARE can be explained by a lack of ciliary Ca2+ influx and, hence, lack of movement of AT1 to the apical membrane by vesicle fusion. In other words, ciliary stimulation may be necessary for externalization of AT1 receptors from intracellular vesicle, at least in highly differentiated cells where microtubules direct apical recycling vesicles to pass through CARE. This concept is summarized in a model in Figure 5.
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Effect of Apical Fluid Movement on AT1 Distribution and Function
To test this hypothesis, confluent mPT monolayers were placed under differentiation conditions on a rotary shaker to gently move the apical solution across the cells. This fluid movement resulted in externalization of AT1 receptors out of CARE and into the apical surface membrane (Figure 6A and 6B). This effect was most pronounced in the center of the filters on which cells were grown.
To assess the functionality of the newly inserted AT1 receptors, phosphorylated extracellular-regulated kinase (pERK) was measured separately in the nucleus and the rest of the cell after Ang II and mechanical stimulation. Immunofluorescence of image stacks that spanned the entire monolayer was quantified, and the ratio of nuclear to total pERK was calculated. Validity of this method was established by calculating the variance of the ratio from several image stacks of each filter (intrafilter variance). The average SEM of 9 sets was 6%, therewith low enough for meaningful comparison of filters treated differently. Interestingly, the ratio of nuclear to total pERK specifically increased only when stimulation with apical Ang II and fluid movement were both present; this effect was mediated by AT1 as indicated by inhibition by the AT1 blocker candesartan (Figure 6C). The numerical results for the ratio under the interesting condition of fluid movements were: control 0.46±0.03; Ang II 0.62±0.02; and candesartan plus Ang II 0.46±0.05, with n=3 different sets of experiments. Differences between the pairs (Ang II)/control and (Ang II)/(Ang II plus candesartan) are statistically significant (P<0.05).
Localization of Other Apical Proteins in Highly Differentiated Proximal Tubule Epithelia
The studies with AT1 raised the question whether redistribution with differentiation is unique to AT1 or whether other proteins behave similarly. We specifically studied the localization of AT2, another G-protein coupled receptor, and the apical transporter NHE3. mPT cells stably express endogenous AT2 and NHE3 in both protoepithelial and highly differentiated states, as determined by immunocytochemistry and Western blot analyses. Figure 7A demonstrates for AT2 and Figure 7B for NHE3 that both types of proteins are also collected in the CARE compartment in a manner very similar to AT1 (for NHE3, see also the online supplement Movie II). Membrane trafficking of NHE3 is known to be regulated in vivo, in part by hypertension,24 and to recycle through CARE.25
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Discussion |
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The results of this study are important in several respects. At the cell biology level, they extend the concept of specialized CARE to proximal tubule cells and important endogenous receptors and transporters. The importance of CARE for trafficking of integral apical membrane proteins and polarization had previously been shown mainly with a collecting duct cell line20 (ie, in MDCK cells and with transfected proteins).21 The present study demonstrates its existence in proximal tubule cells and at physiological abundance of the endogenous AT1 and AT2 receptors and NHE3 transporter. Furthermore, the importance of microtubule organization for formation of CARE is shown, and its proximity to the primary cilium and the formation of a specialized apical membrane region devoid of WGA-binding proteins is demonstrated for the first time to our knowledge. A specialized apical membrane region, adjacent intracellular accumulation of specific proteins, or both have previously been demonstrated a few times in other epithelial monolayers (eg, SNAP-25 in MDCK cells,26 NHE3 in opossum kidney cells,25 and aminopeptidase N in a proximal tubule cell line).27 However, no function has been established. The coordinated development of the microtubule ring structure, the accumulation of vesicles containing integral apical membrane proteins, and a specialized apical membrane region adjacent to the cilium with differentiation suggest that the architecture of the microtubule cytoskeleton and distribution pattern of the apical glycoproteins are useful criteria to judge the differentiation state of epithelial cells.
At the functional level, the studies establish that fluid flow is important for directing AT1 receptors to the apical surface and allowing them to interact with the hormone Ang II in the adjacent solution to produce cellular signals appropriate for this receptor. The presence of AT1 in the CARE compartment adjacent to the cilium would appear to be important for control of externalization of this receptor by fluid flow and ciliary deflection. Assuming that proximal tubule cilia respond in the same manner as MDCK and collecting duct cells (ie, with localized Ca2+ influx), ample precedence from other cell types suggests that this Ca2+ can promote fusion of nearby vesicle with the plasma membrane (Figure 5). Interestingly, the specialized apical plasma membrane region adjacent to the cilium and devoid of WGA-binding resembles the specialization of the flagellar pocket in trypanosoma,28 which has been established as a major site for exo- and endocytosis.
The results on AT1 trafficking clearly demonstrate that AT1 externalization of the receptor can be rate-limiting for Ang II signaling and that the dynamics of externalization and endocytosis must be taken into account when considering the situation in vivo. The steady-state situation in vivo is one of fluid flow and constant Ang II secretion into the lumen and, hence, tonic Ang II signaling. Interestingly, expected differences in cell behavior in response to either tonic or acute stimulation can explain differences in the dose-response curve of Ang II on sodium bicarbonate reabsorption with different experimental preparations, particularly between in vivo and in vitro preparations. In vivo, increasing Ang II concentrations monotonically stimulate sodium bicarbonate reabsorption rates up to 2.5-fold above the Ang II-independent ones.29,30 In contrast, in the examined in vitro preparations, the Ang II dose-response is biphasic with stimulation at very low concentrations and inhibition at higher concentrations, such that at physiological luminal concentrations only minimal stimulation or even inhibition of sodium bicarbonate reabsorption occurs.31 The biphasic curve results from activation of different cellular signaling pathways by AT1,32,33 one that is stimulatory at low Ang II concentrations and another one that is inhibitory at higher concentrations. Interestingly, with tonic stimulation by Ang II and recycling of the angiotensin receptor through the cell, as it occurs in vivo, the concentration of the active Ang II-receptor complex at any time should remain modest even at high Ang II concentrations, thus predicting coupling to only the stimulatory signaling pathway and, hence, a monotonic stimulatory curve. Similarly, the proposed mechanism for Ang II signal activation in Figure 5 allows for shifts in the rate-limiting step depending on preparation and condition, and such a shift can explain the wide dynamic range of Ang II effects on Na+ absorption (6 orders of magnitude from 10–12 to 10–6 mol/L) in different proximal tubule preparations.34,35
It is unclear at the moment what the dominant functional consequences of basolateral AT1 signaling are. Kreitzer et al36 convincingly showed that integral "apical" membrane proteins can be inserted into the basolateral plasma membrane of polarized MDCK cells when trafficking is altered by microtubule disrupting procedures, such as exposure to cold or treatment with microtubule disrupting agents. Therefore, AT1 receptors would be expected to reach the basolateral plasma membranes under any condition that would disrupt the normal microtubule architecture, including inflammatory processes. It is interesting to speculate that healthy proximal tubule cells may have evolved microtubule-dependent trafficking of AT1 to direct this receptor away from the basolateral membrane and to concentrate on signal transduction that effects sodium retention.
Perspectives
The results of this study have implications for the mechanism of intrarenal regulation of sodium reabsorption by Ang II. Ciliary control of the movement of angiotensin receptors to the apical surface membrane in proximal tubule cells provides a rationale why the kidney constitutively maintains high luminal Ang II concentrations. Trafficking of apical Ang II receptors through CARE, control of their externalization by ciliary movement, and high luminal Ang II concentrations constitute a mechanochemical signal transduction scheme and thus serve to provide cells with pressure/flow information. Ample ligand (Ang II) in the luminal fluid is necessary so that subsequent ligand binding, downstream signaling, and receptor endocytosis are fast relative to externalization. Furthermore, this complex regulatory scheme allows integration of different types of signals. For example, proximal tubule cells have recently been shown to sense cytosolic Na+ concentrations and respond with appropriate changes in the ratio of expression of AT1 and the dopamine receptor D1,37 which regulate Na+ reabsorption in opposite directions. The combination of Na+-dependent receptor expression and flow-dependent receptor externalization could provide cells with a mechanism to integrate information on luminal fluid flow and Na+ concentration, that is, information about Na+ abundance.
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Acknowledgments |
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This research was supported by a grant from the Investigator Sponsored Trial Program of Astrazeneca (IRUSCand 0167) and National Institutes of Health (HL-41618). R.J.K. was supported by National Institutes of Health training grant DK07678. Image acquisition and analysis was supported by DK27651. We would like to thank Drs Pamela Davis, Richard Tyler Miller, Elias Veizis, and Cathleen Carlin for meaningful scientific discussions contributing to this work and Sheryl Chow and Margaret Finesilver for their technical assistance. In addition, we thank Dr Janice G. Douglas for introduction to angiotensin II research and support and Dr Surya M. Nauli for model design.
Received March 22, 2004; first decision April 6, 2004; accepted June 14, 2004.
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