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Physiology 20: 86-90, 2005; doi:10.1152/physiol.00002.2005
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Physiology, Vol. 20, No. 2, 86-90, April 2005
© 2005 Int. Union Physiol. Sci./Am. Physiol. Soc.

EMERGING TOPICS

Renal Cell-to-Cell Communication via Extracellular ATP

Peter Komlosi, Attila Fintha and P. Darwin Bell

Departments of Medicine and Physiology, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama

pkomlosi{at}uab.edu


   Abstract
 
In the kidney, macula densa cells communicate with the mesangial cell-afferent arteriolar smooth muscle cell complex through ATP signaling. This signaling process involves release of ATP across the macula densa basolateral membrane through a maxi anion channel and the interaction of ATP with purinergic P2 receptors.


   Introduction
Top
 Introduction
ATP release
 Extracellular ATP degradation
 Purinergic receptors
 Release of ATP by...
 Macula densa ATP signaling
 References
 
More than seventy-five years ago, Drury and Szent-Györgyi first reported the concept that purines act as extracellular signaling molecules (8). Over the intervening years, there has been the increasing awareness that extracellular adenyl purines, including ATP, have important and diverse effects on many biological processes. Critical to this signaling cascade is the presence of extracellular nucleotides. Although nucleotides can be released from injured cells or during cellular necrosis, there is increasing evidence for the regulated release or movement of nucleotides from cell to extracellular fluid. This can result in substantially elevated extracellular nucleotide concentrations within extracellular microdomains adjacent to the point at which the nucleotide is released. Considering the additional fact that extracellular nucleotides, including ATP, undergo rapid enzymatic degradation, it is apparent that the majority of the biological effects of extracellular nucleotides involve localized paracrine or autocrine signaling. Transduction of extracellular nucleotide signaling occurs through specific cell surface expression of nucleotide or purinergic receptors. Thus ATP signaling involves three distinct steps: the first is release of ATP from the cell interior, the second is the extracellular regulation of ATP concentration via degradation, and the third is the binding of ATP to specific receptors.


   ATP release
Top
 Introduction
 ATP release
Extracellular ATP degradation
 Purinergic receptors
 Release of ATP by...
 Macula densa ATP signaling
 References
 
ATP release measured with the luciferin/luciferase bioluminescent assay has been detected from a large number of different types of cells, including polarized epithelial cell lines (40). Several examples of stimuli that lead to the release of ATP are extracellular hypotonicity (32), increases in intracellular calcium concentration ([Ca2+]i) (4), and elevated levels of cell cAMP (30). At the present time, ATP is thought to exit cells through either vesicular transport or channel-mediated release (33). Because ATP is almost exclusively present in its negatively charged form, plasmalemmal anion channels are tempting candidate mediators of extracellular ATP release. Several proteins for this ATP channel have been proposed, including connexin hemichannels, the ATP-binding cassette transporters [including the multidrug resistance protein and CFTR (or associated proteins)], a splice variant of the mitochondrial protein voltage-dependent anion channel (VDAC) (26), and the recently cloned TTYH group of proteins (39). At the present time, however, there is a lack of convincing data conclusively demonstrating that any of these candidate proteins serve as the sole or major pathway for the movement of ATP across the plasma membrane.


   Extracellular ATP degradation
Top
 Introduction
 ATP release
 Extracellular ATP degradation
Purinergic receptors
 Release of ATP by...
 Macula densa ATP signaling
 References
 
Extracellular ATP degradation occurs through at least three different nucleotidases that are anchored to the outside of the cell membrane or secreted into interstitium fluid (44). Ecto-nucleoside trisphosphate di-phosphohydrolases (E-NTPDases) are capable of the sequential removal of a phosphate from ATP and ADP. Ecto-nucleotide pyrophosphatases/phosphodiesterases (E-NPPases) also degrade ATP, giving rise to AMP and pyrophosphate. Ecto-5'-nucleotidase is the enzyme responsible for the final step in ATP degradation via removal of a phosphate group from AMP. It should be emphasized that both the release of ATP via channels and the presence of local degrading enzymes provide for a rapid local signaling process with fast on/off kinetics.


   Purinergic receptors
Top
 Introduction
 ATP release
 Extracellular ATP degradation
 Purinergic receptors
Release of ATP by...
 Macula densa ATP signaling
 References
 
Purinergic receptors that bind extracellular ATP are classified as P2 receptors to distinguish them from P1 receptors that are activated by adenosine. P2 receptors have been localized in almost all mammalian tissue. P2 receptors are subdivided into ionotropic P2X receptors and G protein-coupled P2Y receptor families (6). Activation of the more common P2Y receptors gives rise to inositol trisphosphate (IP3)-mediated Ca2+ mobilization, whereas the P2X receptor is a nonselective cation channel that is permeable to Ca2+. There are multiple members of both P2X and P2Y receptor families, and these individual isoforms differ in tissue distribution, affinity for nucleotides, and antagonists/agonist specificities. Recent studies suggest that various isoforms within the P2X and P2Y families can also form multimeric complexes (23). For further information and details on purinergic receptors, the reader is referred to several review articles in the references (19, 37, 43).


   Release of ATP by macula densa cells
Top
 Introduction
 ATP release
 Extracellular ATP degradation
 Purinergic receptors
 Release of ATP by...
Macula densa ATP signaling
 References
 
In kidney, P2X and P2Y receptors are expressed at both the apical and basolateral membranes of renal epithelial cells, in the renal vasculature, and in glomerular mesangial cells and podocytes (42, 43). P2 receptor activation has been suggested to play a role in a number of renal processes, including the regulation of renal hemodynamics and tubular transport function. We have been interested in the role of ATP and P2 receptors in a signaling process that occurs between a specialized renal epithelial cell, called a macula densa cell, and the adjacent mesangial cell/afferent arteriolar complex.

The macula densa plaque is a unique population of cells that are in the thick ascending limb at the point where this segment returns to the glomerulus (FIGURE 1Go). The apical membrane of these cells is exposed to tubular fluid flow, whereas the basolateral membrane is in contact with mesangial cells. These cells play a pivotal role in monitoring tubular fluid flow and composition and transmitting this information to the renal vasculature. Because of the transport of NaCl by the water-impermeable thick ascending limb, tubular fluid NaCl concentration ([NaCl]) is low but can be elevated in response to increases in tubular flow rate. Macula densa cells detect increases in tubular fluid [NaCl] and transmit signals that cause smooth muscle cell contraction of the afferent arteriole, resulting in decreases in glomerular filtration rate, a mechanism that is called tubuloglomerular feedback (TGF). Because there is a lack of specialized junctions or connections between macula densa cells and the adjacent mesangial cells, it has been presumed that a chemical mediator is responsible for the signaling that occurs between these two cell types; however, the nature of this mediator has remained elusive.



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  		FIGURE 1. Sensory input for macula densa signaling
A: schematic diagram of a nephron. B: increases in flow rate increase luminal NaCl concentration ([NaCl]L) OSML, luminal osmolality. C: relationship of the macula densa, mesangial cells, and afferent arteriolar smooth muscle cells. The nature of the chemical mediator that is released by the macula densa cells and that transmits information to the other components in this pathway remains unknown. D: three-dimensional reconstruction of the perfused living TAL-macula densa segment. An animated supplement to this figure is available at http://physiologyonline.physiology.org/cgi/content/full/00002.2005/DC1.

 
The reason to consider ATP as a mediator of macula densa cell signaling was due, in part, to the elegant work of Inscho (13–16) and also Navar et al. (21, 22, 24, 25) in defining the importance of P2 receptors in the control of the renal vasculature (see below). Also, macula densa cells express very high levels of mitochondria and low levels of basolateral Na+-K+-ATPase. Presumably these cells would have a high capacity to generate ATP and low energy utilization, at least in terms of transporting NaCl across the basolateral membrane. As shown in FIGURE 2Go, isolated macula densa plaques that were still adherent to the glomerulus were subject to patch clamping to identify channels at the lateral membranes of these cells. We were particularly interested in a large channel (~380 pS) that was identified to be anion conductive. It displayed a very prominent voltage inactivation at voltages in excess of ±40 mV. Both the size and the biophysical properties of this channel were very similar to those reported for VDAC, a channel that conducts ATP across mitochondrial membranes. In inside-out patches from lateral membranes of macula densa cells, this plasma membrane large maxi anion channel was also ATP conductive, as shown in FIGURE 2Go. Furthermore in cell-attached patches, raising bath [NaCl] from ~25 to 150 mM markedly increased maxi anion channel activity, which would be consistent with an ATP signaling process that could be involved in TGF signaling.



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  		FIGURE 2. Detection of macula densa ATP release
A: photomicrograph of a preparation used in macula densa basolateral patch-clamp experiments. Holding and patch pipettes are also shown. B: single-channel current-voltage curves from inside-out patches when the bath contained either Ringer’s solution or a solution containing ATP. C: representative tracing demonstrating channel activity generated by ATP influx into the pipette at a potential of –50 mV. The arrowhead represents the closed state of the channel. D: photomicrograph showing a preparation used in the biosensor experiments. In an isolated perfused TAL in which the glomerulus was partially removed, thereby exposing the basolateral membrane of macula densa plaque, a fura-2-loaded biosensor cell (pseudocolored to represent the green fluorescence at the fura-2 emission wavelength) was positioned and held with a holding pipette at the basolateral membrane of the macula densa. E: in response to an increase in [NaCl]L, there was an increase in the biosensor fura-2 ratio, indicating the activation of P2X receptors and increases in the cytosolic calcium concentration.

 
To further investigate ATP signaling by macula densa cells, we employed a novel purinergic biosensor technique. This involved using PC12 cells that express P2X receptors and either by monitoring channel activity using the patch-clamp technique or by loading these cells with fura-2 and measuring [Ca2+]i. As shown in FIGURE 2Go, this biosensor cell was placed at the basolateral membrane of macula densa cells, and ATP release was observed upon increases in luminal [NaCl] (3). We found that the ATP release across the basolateral membrane of macula densa cells was consistent with its role in macula densa cell signaling. ATP release increased in proportion to luminal [NaCl], it was inhibited by blocking salt transport by macula densa cells with furosemide, and [NaCl]-dependent ATP release did not occur in cortical thick ascending limb cells. Also, the release of ATP was enhanced from macula densa preparations obtained from animals maintained on a low-salt diet (18), which is consistent with the upregulation of TGF that occurs during salt restriction. Thus these studies demonstrate that there is a local paracrine signaling process that involves ATP release across that basolateral membrane of macula densa cells.

What activates this ATP-conductive pathway with elevations in luminal [NaCl] remains to be discovered. Possible candidates are based on previous work in macula densa cells, which found that increases in [NaCl] cause elevations in macula densa intracellular concentrations of sodium (27), chloride (34, 35), and calcium (28); basolateral membrane depolarization (1); changes in cell volume (10, 11, 20, 29); and intracellular alkalinization (9). The answer to this question remains an active area of research.


   Macula densa ATP signaling
Top
 Introduction
 ATP release
 Extracellular ATP degradation
 Purinergic receptors
 Release of ATP by...
 Macula densa ATP signaling
References
 
Once released across the macula densa basolateral membrane, the exact role of extracellular ATP in signaling through the extraglomerular mesangial cell field and to the smooth muscle cells of the afferent arteriole is controversial. Mesangial cells and afferent arteriolar smooth muscle cells possess P2 receptors, and this entire area of the juxtaglomerular apparatus contains abundant nucleotidases that would lead to the degradation of ATP. This would appear to be important because TGF signaling has relatively fast kinetics (on the order of seconds) and thus would require rapid termination of ATP signaling. It is also possible that the rapid ATP degradation leads to the formation of adenosine and that subsequent P1 receptor activation plays a role in TGF signaling. Supporting this concept are studies by several groups (5, 7, 36, 38, 41) showing that TGF responses are inhibited if A1 adenosine receptors or the adenosine-producing enzyme 5'-nucleotidase are pharmacologically blocked or genetically disrupted. What has not been entirely ruled out is the possibility that P1 receptor activity or integrity may play more of a permissive role in TGF signaling.

In this regard, Nishiyama et al. (24, 25) reported that renal interstitial concentration of ATP but not of adenosine parallels TGF-dependent adjustments in renal vascular resistance during changes in perfusion pressure. Also, interstitial infusion of ATP, probably via desensitizing P2 receptors, blocks TGF responses (22). In addition, as proposed by Inscho et al. (14), ATP-mediated activation of P2X1 receptors is a prerequisite for TGF-dependent autoregulatory afferent arteriolar vasoconstriction. Therefore, ATP can readily diffuse to the smooth muscle cells of the afferent arteriole and bind to P2X1 and/or P2Y2 receptors and thereby produce afferent arteriolar vasoconstriction (FIGURE 3Go).



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  		FIGURE 3. Role of ATP in macula densa cell signaling
A: membrane transport events in macula densa cells that lead to the detection of changes in [NaCl]L and [OSM]L by these cells (2). B: an increase in [NaCl]L leads to an array of intracellular signaling events in the macula densa cells, which, in turn, increases basolateral maxi anion channel activity and the release of ATP into the cleft beneath the extraglomerular mesangial cells. ATP can then activate P2 receptors on the mesangial cells or on the vascular smooth muscle cells of the afferent arteriole. C and D: the relationship between TGF responses (downward curve representing decreases in GFR) and the associated increases in macula densa ATP that occur over the same range of [NaCl]L.

 
ATP released across the basolateral membrane can cause increases in mesangial [Ca2+]i via P2 receptor activation. This has clearly been shown in studies in which cultured mesangial cells and not PC12 cells were used as biosensor cells in macula densa ATP-signaling experiments. Also, as reported by Gutierrez et al. (12), adenosine alone or P1 receptor activation does not lead to increases in mesangial [Ca2+]i. Because mesangial cells and the smooth muscle cells of the afferent arteriole are interconnected via gap junctions, it seems logical that one component of TGF signaling involves P2 receptor-mediated signaling through the mesangial cell field and to the smooth muscle cells of the afferent arteriole. This paradigm is supported by the demonstration that abrogation of mesangial cells inhibits TGF responses in vitro (31). However, additional studies are needed to fully clarify the role of P1 and P2 purinergic receptors in macula densa TGF signaling. In this regard, it has recently been reported that the distribution of ATP-degrading enzymes closely correlates with the expression pattern of P2 receptors, suggesting that ATP degradation might be necessary for P2 receptor activation to happen (17). In other words, juxtaglomerular vascular function may depend on the concerted interplay of P1 and P2 purinergic activation.


   Acknowledgments
 
Special thanks to Martha Yeager for secretarial assistance.

This work was supported by a grant from the National Institute of Diabetes and Digestive and Liver Diseases (DK-32032) to P. D. Bell.


   References
Top
 Introduction
 ATP release
 Extracellular ATP degradation
 Purinergic receptors
 Release of ATP by...
 Macula densa ATP signaling
 References
 

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