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J Am Soc Nephrol 13:1145-1151, 2002
© 2002 American Society of Nephrology

Purinergic Receptor Signaling at the Basolateral Membrane of Macula Densa Cells

Ruisheng Liu*, P. Darwin Bell{dagger}, Janos Peti-Peterdi{dagger}, Gergly Kovacs{dagger}, Alf Johansson* and A. Erik G. Persson*

*Department of Physiology, Uppsala University, Uppsala, Sweden; and {dagger}Division of Nephrology, Nephrology Research and Training Center, and Departments of Medicine and Physiology, University of Alabama at Birmingham, Birmingham, Alabama.

Correspondence to: Dr. A. Erik G. Persson, Department of Physiology, Biomedical Center, Box 572, S-75123, Uppsala, Sweden. Phone: +46-18-4714180; Fax: +46-18-4714938; E-mail: erik.persson{at}physiology.uu.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
ABSTRACT. Purinergic receptors are important in the regulation of renal hemodynamics; therefore, this study sought to determine if such receptors influence macula densa cell function. Isolated glomeruli containing macula densa cells, with and without the cortical thick ascending limb, were loaded with the Ca2+ sensitive indicators, Fura Red (confocal microscopy) or fura 2 (conventional video image analysis). Studies were performed on an inverted microscope in a chamber with a flow-through perfusion system. Changes in cytosolic calcium concentration ([Ca2+]i) from exposed macula densa plaques were assessed upon addition of adenosine, ATP, UTP, ADP, or 2-methylthio-ATP (2- MeS-ATP) for 2 min added to the bathing solution. There was no change in [Ca2+]i with addition of adenosine (10-7 to 10-3 M). UTP and ATP (10-4 M) caused [Ca2+]i to increase by 268 ± 40 nM (n = 21) and 295 ± 53 nM (n = 21), respectively, whereas in response to 2MesATP and ADP, [Ca2+]i increased by only 67 ± 13 nM (n = 8) and 93 ± 36 nM (n = 14), respectively. Dose response curve for ATP (10-7 to 10-3 M) added in bath showed an EC50 of 15 µM. No effect on macula densa [Ca2+]i was seen when ATP was added from the lumen. ATP caused similar increases in macula densa [Ca2+]i in the presence or absence of bath Ca2+ and addition of 5 mM ethyleneglycotetraacetic acid (EGTA). Suramin (an antagonist of P2X and P2Y receptors) completely inhibited ATP-induced [Ca2+]i dynamics. Also, ATP-Ca2+ responsiveness was prevented by the phospholipase C inhibitor, U-73122, but not by its inactive analog, U-73343. These results suggest that macula densa cells possess P2Y2 purinergic receptors on basolateral but not apical membranes and that activation of these receptors results in the mobilization of Ca2+.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The tubuloglomerular feedback (TGF) mechanism is a very important regulator of renal hemodynamics. This mechanism operates as a negative feedback loop, sensing changes in distal nephron fluid flow rate by detecting flow-dependent alterations in luminal sodium chloride concentration ([NaCl]) at the macula densa. Signals are then sent by the macula densa cells, which contract the afferent arteriole, thereby adjusting the level of GFR and renal blood flow (1–3). Furthermore, macula densa cells can also influence release of renin from the granular cells in the afferent arteriole (4). The primary mechanism by which the macula densa cells detect changes in [NaCl] is through an apically located Na:2Cl:K cotransport mechanism (5,6).

It has also been found that the sensitivity of this TGF mechanism can be reset by a large number of different factors. For instance, renal interstitial pressure and angiotensin II are potent regulators of TGF sensitivity (7,8). Nitric oxide, prostaglandin, thromboxanes, and many other local factors and hormones can also influence the sensitivity of the TGF mechanism (9). The site(s) at which all these factors exert their influence is not well understood. One possibility is that modulation of TGF can occur at the level of the macula densa cells, and it is therefore of particular interest to investigate the receptors expressed by macula densa cells and what effects occur in these cells with receptor activation. For instance, it has recently been reported that macula densa cells possess AT1 receptors for angiotensin II and that activation of these receptors increases sodium-proton exchange of the apical NHE2 isoform (10–12).

Purinergic receptors have been identified as playing a large role within the juxtaglomerular apparatus (13). These receptors are activated by extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) and are important signaling molecules that mediate various biologic effects in the kidney. They may serve as paracrine regulators of renal microvascular resistance (14,15) and may modulate mesangial cell contraction, alter epithelial ion transport, and influence the TGF mechanism (16–20) via cell surface receptors for purines.

There are two main families of purine receptors: adenosine or P1 receptors and P2 receptors, the latter recognizing primarily ATP, ADP, UTP, and UDP (21). On the basis of differences in molecular structure and signal transduction mechanisms, P2 receptors are divided into two families consisting of ligand-gated ion channel-receptors and G-protein-coupled receptors termed P2X and P2Y receptors, respectively. Seven mammalian P2X receptors (P2X1–7) and five mammalian P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) have been cloned (22). Activation of both receptors increases cytosolic calcium concentration ([Ca2+]i); the difference being that P2X receptors induce Ca2+ influx while P2Y receptors result in Ca2+ mobilization. In addition, these receptors have been reported to be expressed in numerous, if not all, nephron segments. Mesangial cells contain P2Y2 receptors (23). The cortical thick ascending limb (cTAL) and collecting ducts express both P2Y1 and P2Y2 receptors (19,24,25). Proximal tubules express the P2Y1 type (26). In outer medullary collecting duct, P2Y1, P2Y2, and P2Y4 receptors are expressed (27).

At this time, the existence and type of purinergic receptors expressed by macula densa cells are unknown. In addition, it has been suggested that macula densa [Ca2+]i may be involved in TGF signaling (1,3,28,29); therefore, it is important to determine if ATP and related nucleotides increase [Ca2+]i in these cells. Finally, we functionally determined if purinergic receptors were preferentially located at the apical or basolateral surfaces of macula densa cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental Preparation
Female New Zealand White rabbits weighing 1.0 to 1.5 kg were killed, and the left kidney was removed and cut into several 1.5- to 3-mm transversal slices. These slices were placed in chilled low-NaCl buffer solution containing 35 mM NaCl, 1.3 mM CaCl2, 1 mM MgSO4, 1.6 mM K2HPO4, 5 mM glucose, 20 mM Hepes with pH adjusted to 7.4, and sufficient sucrose was added to achieve an osmolality at 290 mOsm. Glomeruli with attached cTAL and containing the macula densa plaque were isolated by microdissection at 4°C under a dissection microscope (Wild, Glattbrugg, Switzerland). In some experiments, the cTAL was carefully removed, leaving the macula densa plaque attached to the glomerulus. In other experiments, the cTAL was left intact for microperfusion studies.

Fluorescence Probe Loading
The fluorescence Ca2+ indicator fura 2 was used for video imaging, and Fura Red was used for confocal microscopy. Macula densa cells were loaded in the low-NaCl buffer solution using 20 µM Fura Red AM with 0.2% pluronic acid or 10 µM fura 2 AM in 1% DMSO for 30 min at room temperature.

Visualization of Macula Densa Cells
Each preparation was then transferred to a chamber fixed to the stage of a Nikon (Tokyo, Japan) microscope attached either to an Applied Imaging QC-700 system (Applied Image Co., Sunderland, England; fura 2 loaded samples) or a Noran Odyssey laser confocal system (Noran, Fura Red-loaded samples). Glass holding pipettes (outer tip diameter, 30 to 40 µm) connected to micromanipulators (MM3, Narishige, Middleton, WI) were used to position the glomerulus so that the macula densa plaque was clearly visible.

Measurement of Cytosolic Calcium Concentration ([Ca2+]i)
Fura Red-loaded macula densa-glomerular preparations were transferred to a Noran Odyssey laser confocal system, which was equipped with an argon-ion laser. A Nikon 60/1.2 water-immersion objective lens was used to visualize macula densa cells. The image size was set to 640 x 480 pixels. The confocal slit was set at a width of 25 nm. Photobleaching was kept to a minimum by maintaining laser intensity at below 30% of maximum and using a shutter so that the preparation was exposed to laser light only during the collection of images. Data collection with the Noran Odyssey confocal system is controlled by a Silicon Graphics workstation. Image acquisition was limited to 30 frames/s and, image noise was reduced when necessary by averaging or summing 16 to 32 individual images. Sampling time for each pixel was 100 ns. Fura Red was excited at 488 nm with the argon-ion laser while emitted fluorescence was recorded at wavelengths of >600 nm through a 550-nm-long pass barrier filter. Relative changes of [Ca2+]i were calculated by a normalization procedure to obtain a "pseudo ratio" (the actual fluorescence intensity level was normalized by the resting level: F-Frest/Frest).A laser transmitted image was recorded at the end of each experiment (Figure 1).



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  		Figure 1. Confocal microscopic image of macula densa cells loaded with Fura Red. (A) Pseudo-colored fluorescence of Fura Red in macula densa cells under control condition and before application of ATP. (B) With the addition of ATP, there is a noticeable decrease in fluorescence, which signifies an increase in [Ca2+]i. (C) After removal of ATP, there is an increase in fluorescence, which indicates that [Ca2+]i has decreased. (D) Transmitted light image of macula densa-TAL preparation.

 
Other studies used conventional video imaging techniques to measure macula densa [Ca2+]i. Fura 2, loaded into macula densa cells, was alternately excited with light at 340 nm and 380 nm, and emitted fluorescence was obtained at 510 nm using the Applied Imaging QC-700 system. The fluorescence ratio (340 nm/380 nm) was converted to [Ca2+]i, and digital imaging of [Ca2+]i was displayed using standard pseudo-color techniques. This system was calibrated using cell-free solutions (Calibration Kit from Molecular Probes Inc.).

Experimental Protocol
Series 1.
For these experiments, the cTAL was removed from the preparation, leaving the macula densa cells directly exposed to the bathing solution. Experiments were performed at 37°C with continuous perfusion of the low-NaCl buffer solution at a rate of 6 to 7 ml/min driven by an infusion pump (PD 5001, Heidolph, Germany). After control measurements of [Ca2+]i were performed, the low-NaCl buffer solution was changed to the same solution but containing one of the following agonists for 2 min: adenosine, ATP, UTP, ADP, or 2-methylthio-ATP (2-MeS-ATP), each at a concentration of 10-4 M. Thereafter, the bathing solution was changed back to the control solution for 15 min before the next agonist was tested. For the Ca2+-free solution, CaCl2 was replaced by 5 mM ethyleneglycotetraacetic acid (EGTA).

Series 2.
Individual cTALs with attached glomeruli were dissected and perfused as described previously (30,31). The cTAL was cannulated and perfused with the low NaCl buffer solution. The preparation was bathed continuously in a normal Ringer solution (containing 135 mM NaCl, 1.3 mM CaCl2, 1 mM MgSO4, 1.6 mM K2HPO4, 5 mM glucose, and 20 mM Hepes; pH was adjusted to 7.4, and osmolality was 290 mOsm) at a rate of 6 to 7 ml/min. Macula densa cells were loaded with fluorescence probe from the luminal side. The following studies were performed: (1) apical and basolateral effects of ATP (10-4 M) by adding this nucleotide to either the perfusate or to the bath; (2) addition of suramin (10-4 M) to the bath for 15 min followed by the addition of ATP (10-4 M); (3) addition of the phospholipase C inhibitor, U-73122 (10-6 M), or its inactive analog, U-73343 (10-6 M), to the bath for 30 min followed by the addition of ATP (10-4 M); (4) ATP or adenosine ranging from 10-3 to 10-7 M was added to the bath and lumen, respectively.

Chemicals
Fura 2 AM and Fura Red AM were from Molecular Probes Inc., Eugene, OR. All other chemicals were from Sigma.

Statistical Analyses
A paired t test (two-tail) was used where appropriate. The level of significance was set at P < 0.05. Data are presented as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1 is an image of the macula densa obtained by confocal microscopy showing the effect of ATP on [Ca2+]i. As opposed to fura 2, in which the ratio of excitation at 340 nm/380 nm increases with elevations in [Ca2+]i, Fura Red is just the opposite, i.e., the fluorescence signal decreases with increases in [Ca2+]i. ATP administration caused rapid and reversible increases in [Ca2+]i. In 32 of 49 experiments, macula densa [Ca2+]i increased upon the initial application of ATP. The other 17 macula densa preparations, which were not affected by ATP, were discarded. The reason that some preparations failed to respond to ATP is not known. It is possible that, in some preparations, ATP could be restricted from gaining access to the macula densa basolateral membrane as a result of the tight adherence of the underlying mesangial cells. It is also possible that some preparations exhibited high nucleotidase activity that resulted in the breakdown of ATP. In those experiments in which ATP caused an increase in [Ca2+]i, a second ATP application led to nearly an identical response (>95%) if there was >=15 min between ATP applications. Shorter time intervals between applications resulted in smaller increases in [Ca2+]i, presumably the result of receptor desensitization (16,32). For the studies shown in Figure 2A, a control ATP-mediated increase in [Ca2+]i was first obtained, followed by adenosine, ATP, UTP, ADP, or 2Mes-ATP administered in a random order. The results are expressed as a percent of the increase in the delta change ({Delta}) in intensity compared with the initial application of ATP. As indicated in Figure 2A, macula densa [Ca2+]i did not change with addition of adenosine to the bath. The largest increase in [Ca2+]i was obtained with UTP (115 ± 23%) followed by ATP (98 ± 15%), whereas only small increases in [Ca2+]i were obtained with ADP (28 ± 6%) and 2Mes-ATP (32 ± 7%).



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  		Figure 2. (A) The effect of nucleotides on macula densa [Ca2+]i using confocal microscopy and Fura Red. Values are expressed as a percent of the delta change in fluorescent intensity obtained with the initial application of ATP. UTP and ATP produced the largest increases in [Ca2+]i, whereas ADP and 2Mes-ATP produced only small changes in [Ca2+]i (P < 0.05 compared with the response to ATP and UTP). There was no response to adenosine. ATP had similar effects on [Ca2+]i in the presence or absence of bath Ca2+ (P > 0.05). (B) Macula densa [Ca2+]i assessed with fura 2 and using video imaging. The pattern of macula densa Ca2+ responsiveness was similar to what was obtained with the confocal system.

 
Using the video imaging system and fura 2, 10-4 M ATP increased [Ca2+]i in 57 of 71 macula densa preparations. The use of fura 2 provided for ratiometric imaging, therefore allowing calculations of [Ca2+]i in absolute values. As shown in Figure 2B, basal [Ca2+]i in macula densa cells was 126 ± 25 nM. {Delta}[Ca2+]i in response to ATP and UTP were 268 ± 40 nM and 295 ± 53 nM, respectively, whereas {Delta}[Ca2+]i in response to 2MesATP and ADP were 67 ± 13 nM and 93 ± 36 nM, respectively. When Ca2+ was removed and 5 mM EGTA added to the bathing solution, the increase in [Ca2+]i in response to ATP was not significantly different from that obtained in the presence of 1.3 mM Ca2+ in the bath (Figure 2).

In microperfusion experiments (Table 1) with video imaging (n = 27), macula densa {Delta}[Ca2+]i increased by 274 ± 32 nM when ATP was added to the bathing solution. In contrast, ATP failed to alter [Ca2+]i when it was added to the luminal perfusate (n = 23). Suramin (n = 7) completely inhibited ATP-induced [Ca2+]i responses. Also, the Ca2+ response was prevented by the phospholipase C inhibitor, U-73122 (n = 6), but not by its inactive analog, U-73343 (n = 9).


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  		Table 1. Changes in macula densa [Ca2+]i with ATP, P2 receptor antagonist, and phospholipase C inhibitora
 
Figure 3 shows that the rise in [Ca2+]i induced by ATP was dose-dependent. The half-maximal increase was obtained with 15 µM ATP, whereas maximal activation was achieved in the presence of 230 µM ATP in the bath. Adenosine (10-7 to 10-3 M) failed to alter macula densa [Ca2+]i when added to either the lumen or the bath.



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  		Figure 3. Dose-response relationship of [Ca2+]i versus ATP or adenosine. There was a sigmoid increase in [Ca2+]i as ATP concentration was elevated, whereas adenosine at any concentration had no effect on [Ca2+]i.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In tubuloglomerular feedback signal transmission, macula densa cells play the central role of sensing changes in tubular fluid composition and transmitting signals, which alter vascular resistance and renin release. The first step in this sensing process involves electrolyte transfer from the lumen to the macula densa cells via the Na:2Cl:K cotransporter (5,6). The cellular events that occur as the result of a change in NaCl entry into macula densa cells have not been completely worked out (28,29), although it is possible that intracellular messenger systems such as Ca2+ may be involved in this signaling pathway. It is therefore of importance to investigate the mechanisms that may control or influence [Ca2+]i and Ca2+ signaling in these cells, such as purinergic receptors.

This study is the first to use real time laser-scan confocal microscopy to study macula densa cells. Confocal microscopy has the advantage of much better spatial resolution (Figure 1) compared with conventional image analysis systems. As shown in Figure 1, it is possible to obtain very detailed images of macula densa cells and other structures that are associated with these cells. It should be possible, in the future, to use confocal microscopy to study subcellular domains within macula densa cells and, importantly, to study the area of contact between the basolateral membrane of macula densa cells and the underlying mesangial cells. In the present studies, addition of ATP caused changes in Fura Red fluorescence that are consistent with an elevation in [Ca2+]i during administration of ATP. However, the use of Fura Red, which is a single wavelength excitation dye, precluded absolute measurements of [Ca2+]i (32). Therefore, additional studies were performed using a conventional imaging system and fura 2, which is a ratiometric dye. Using fura 2, it is possible to estimate baseline and dynamic changes in [Ca2+]i.

In these studies, we found no increase in [Ca2+]i during the administration of adenosine (10-7 to 10-3 M). In a previous micropuncture study in the rat (20,33), an adenosine A1 receptor agonist was found to enhance TGF responses when added from the lumen. In their studies (20,33), it is possible that the A1 receptor agonist directly affected the arteriolar smooth muscle cells. As recently reported (23,34), freshly dissected renal arterioles but not cultured mesangial cells respond to adenosine with an increase in [Ca2+]i. Alternatively, it is possible that macula densa cells do possess adenosine receptors but that these receptors are not wired to the intracellular Ca2+ messenger system.

In our studies, we found that ATP and UTP produced large increases in [Ca2+]i and that ADP and 2MesATP produced only small increases in [Ca2+]i. This is consistent with the presence of P2Y receptor expression. P2Y receptor isoforms of the purinergic receptor family are coupled to G-proteins and act through the PLC-IP3 pathway to mobilize Ca2+ from intracellular storage sites (35). The usual scenario of agonist-induced increases in [Ca2+]i for G-protein-coupled receptors is a peak elevation in [Ca2+]i, due to Ca2+ mobilization. This is followed by a lower sustained increase in [Ca2+]i that is at least partially due through Ca2+ entry (36). Therefore, the early maximal increase in [Ca2+]i is a good indicator of release of Ca2+ from intracellular pools. For this reason, our results are reported as the maximal increases in [Ca2+]i obtained with each agent.

We found that there was no significant difference in the elevation of [Ca2+]i obtained with addition of ATP in the presence or absence of bath Ca2+. Also, increases in Ca2+ were prevented by the phospholipase C inhibitor, U-73122, but not by its inactive analog, U-73343. These findings strongly support our conclusion that the most important contribution to the rapid and maximal increase in [Ca2+]i was from Ca2+ mobilization through the PLC-IP3 pathway and not through Ca2+ entry mechanisms (37–39). It also further supports the presence of P2Y receptors and not P2X receptors in macula densa cells. This later class of receptors exhibits properties of a nonselective cation channel that promotes increases in [Ca2+]i via Ca2+ entry (40).

Other studies were performed to determine if there was a sidedness to the effects of purinergic receptor activation in macula densa cells. This can be readily accomplished by maintaining the TAL intact during dissection and performing in vitro microperfusion studies. In this manner, nucleotides could be discretely delivered to either the apical surface from the lumen or to the basolateral surface from the bath. We found that ATP increased [Ca2+]i only when added to the bath and not to the lumen. Thus, in macula densa cells, the major effects of ATP occur at the basolateral membrane.

The order of the efficacy of the nucleotides in macula densa cells was essentially the same as that found for P2Y2 and/or P2Y4 receptors (23,41–44); however, this assertion should be viewed with caution. It should be kept in mind that there are complicating factors inherent in functional methods used in establishing purinergic receptor subtypes (45). In addition, there is a lack of inhibitors with specificity for the various P2Y receptor isoforms. Pharmacologic characterizations of P2Y2 and P2Y4 are almost the same, except P2Y4 receptors are less sensitive to suramin (46,47). Our results showed that suramin could completely block the [Ca2+]i responses induced by ATP, so we conclude the macula densa cells express P2Y2 receptors.

The EC50 of ATP is 15 µM in present study, which is higher than that reported in other studies, which ranged from 1 µM to 10 µM (48–50). The reason for this is not clear, but it is possible that the sensitivity of these receptors might vary in different tissues. In addition, the tight adherence of the underlying mesangial cells to the macula densa plaque might hinder access of ATP to the macula densa basolateral membrane. These factors may also help to explain why a fraction of preparations failed to respond to ATP administration. However, the important point is that low micromolar amounts of ATP are released across basolateral membrane of macula densa cells as directly assessed using a biosensor technique. Thus, taken together, these results suggest that ATP may function in an autocrine manner at the macula densa.

What role could macula densa P2Y2 receptors play in TGF signaling? As indicated, it was recently reported (51) that, in response to an increase in luminal [NaCl], macula densa cells released ATP in micromolar amounts across the basolateral membrane. This occurred via maxi-anion channels that were also shown to be permeable to ATP by patch clamp analysis. It was proposed that ATP might serve in feedback signal transmission because mesangial cells express purinergic receptors. It is also possible that ATP released from macula densa cells may play an autocrine role feeding back and activating P2Y2 receptors on macula densa cells. In this manner, ATP may serve in sustaining increases in macula densa [Ca2+]i.


   Acknowledgments
 
This study was supported financially by the Swedish Medical Research Council (project no. K99-14X-03522–28D), the Wallenberg Foundation, Ingabritt and Arne Lundberg Foundation, and the National Institutes of Health: NIDDK 32032 (PDB). Professor Bell received a grant from the WennerGren Foundation to make this study possible.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication October 11, 2001. Accepted for publication February 6, 2002.




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