P2X Receptors And Kidney Function

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Matthew A. Bailey1∗, Robert J. Unwin2, and David G. Shirley2

Accumulating evidence indicates that the ATP/P2 receptor system, acting in an autocrine or paracrine manner, can affect a wide range of renal functions. P2X receptor subunits have been identified in most renal vessels and in every nephron segment; ATP is released from renal epithelial cells, and enzymes responsible for ATP degradation are expressed in the vasculature and tubules. Stimulation of P2X1 receptors in the afferent arterioles by ATP released from renal nerve terminals or from adjacent macula densa cells induces vasoconstriction and contributes to the regulation of renal hemodynamics. In the tubule, there is evidence for a variety of P2X-mediated effects: inhibition of proximal tubular reabsorption; inhibition of Na+K+2Cl− cotransporter activity (via increased nitric oxide synthesis) in the thick ascending limb of the loop of Henle; inhibition of magnesium reabsorption in the distal tubule; and modulation of sodium and water reabsorption in the collecting duct. Finally, P2X receptors, particularly P2X7 subunits, appear to play an important role in renal pathology, specifically for cyst formation in polycystic kidney disease and in renal inflammation. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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INTRODUCTION

Nucleotides and P2 receptors subserve a wide range of physiological roles throughout the body. Although knowledge of autocrine/paracrine effects of this system in the kidneys has lagged behind that of other organs/tissues, the last decade has seen major advances in closing the gap. Thus far, most renal investigations have focused on P2Y receptors1; information about renal P2X receptors and their function is more limited.

SECRETION OF ATP IN THE KIDNEYS

Virtually all cells can release nucleotides, and renal vascular and epithelial cells are no exceptions. Vekaria et al.2 reported intraluminal ATP concentrations in rat proximal convoluted tubules (PCTs) in vivo of 200–300 nmol/L, markedly higher than concentrations in the glomerular filtrate, suggesting secretion of ATP by PCT cells. Using mouse medullary thick ascending limbs (metals) perfused in vitro, Leipziger's group showed that increases in intraluminal pressure resulted in elevations in intracellular Ca2+([Ca2+]i) that were themselves dependent on nucleotide release.3 In a follow-up study, P2Y2 receptor-expressing astrocytes were used as biosensors to demonstrate both spontaneousand agonist-induced nucleotide release. Vasopressin elicited peak intraluminal nucleotide concentrations of 200–300 nmol/L. Since the P2Y2 receptor is unable to discriminate between UTP and ATP, the specific nucleotide(s) released could not be identified. In the same study, Odgaard et al.4 found that vasopressin also triggered nucleotide secretion from mouse cortical collecting duct (CCD) perfused in vitro; intraluminal concentrations again approached 300 nmol/L.

Although these concentrations are probably below the threshold for P2X receptor activation, bulkphase measurements almost certainly underestimate concentrations at the cell membrane, since ectonucleotidases rapidly metabolize secreted nucleotides (see below).

Mechanism(s) of ATP Release

The mechanism of secretion of nucleotides from renal tubular cells is not yet established and may differ from segment to segment. Exocytosis of vesicles containing ATP is one possibility; in addition, a variety of channels/transporters has been implicated.5 Maxi-anion channels mediate ATP transport across the basolateral membrane of macula densa cells in response to increased NaCl delivery6 (see below). Cystic fibrosis transmembrane conductance regulator (CFTR) channels have also been mooted as a route of efflux, but this possibility has not received firm support.5 Evidence for the role of connexin (Cx) hemichannels in the release of ATP in the distal nephron has come from a study using Cx30 knockout mice.7 Partially split-open CCDs were microperfusion in vitro and P2X2 receptor-expressing biosensors were placed in direct contact with the apical membranes of CCD cells. In wild-type mice, increases in tubular flow evoked suramin-sensitive (i.e., nucleotide mediated) increases in [Ca2+] I in the biosensor cells, whereas responses were almost absent in Cx30 knockout mice. However, there are doubts that Cx hemichannels open under physiological conditions. The structurally homologous pannexins, in contrast, can be activated by membrane depolarizations in the physiological range. Pannexins can also form ATPpermeable hemichannels, but further studies will be needed to determine their role, if any, in the kidney.5

ECTONUCLEOTIDASES

Nucleotides released from the renal vasculature and from epithelial cells are rapidly degraded by surfacelocated and soluble enzymes (ectonucleotidases) to different nucleotides or to nucleosides. Four families of ectonucleotidases exist ectonucleoside triphosphate phosphohydrolase (NTPDases), ectonucleotide pyrophosphatase phosphodiesterases (NPPs), ecto-5' -nucleotidase, and alkaline phosphatases. Members of all four families have been identified in the kidney.8 Since the principal ligand for P2X receptors is ATP itself, it is likely that these enzymes have a profound influence on P2X-mediated effects. In addition to enzymes that break down nucleotides, two families of phosphorylating enzymes exist nucleoside diphosphate kinases, which catalyze the transfer of the terminal phosphate of nucleoside 5 -triphosphates to nucleoside 5 -diphosphates, and adenylate kinases, which catalyze the production of ADP from ATP and AMP or vice versa, depending on the concentrations of the respective nucleotides. Although initially believed to be restricted to the cell cytosol, there is evidence that phosphorylating enzymes are also present in the cell membrane.9 The principal catalytic activities of the ectonucleotidases and phosphorylating enzymes expressed in the kidney are summarized in Table 1.

The NTPDase family comprises eight members, four of which (NTPDases 1, 2, 3, and 8) hydrolyze extracellular nucleotides. NTPDase1 hydrolyzes ATP and ADP with almost equal preference, whereas NTPDase2 has a much greater preference for ATP, therefore causing accumulation of ADP; NTPDases 3 and 8 are intermediate in their preference.8 In rats and mice, NTPDase1 is prominent throughout most of the renal vasculature and is also present in the thin ascending limb of Henle and medullary collecting duct (CD). NTPDase2 has been immunolocalized to Bowman’s capsules and to the most nephron segments beyond the proximal tubule; the intrarenal expression of NTPDase3 has been investigated only in the rat where, like NTPDase2, it was found in thick ascending limb (TAL), distal tubule, and CD.8 Information on NTPDase8 is incomplete.

The NPP family comprises seven members, but only NPP1 to NPP3 are able to hydrolyze nucleotides. Information on the intrarenal distribution of NPPs is limited. Staining for NPP1 protein has been identified in mouse proximal tubules and in basolateral membranes of distal tubules; while prominent staining for NPP3 has been found in rat glomeruli and in the apical membrane of the pars recta, but not in more distal segments.8 Ecto-5 -nucleotidase catalyzes the final stage of nucleotide hydrolysis to the nucleoside. It is found in apical membranes of rat PCT and in intercalated cells throughout the distal nephron, as well as the peritubular space.8

Alkaline phosphatase has been identified in the apical membrane of PCT and pars recta of rat kidneys. Although alkaline phosphatases have broad substrate specificity, capable of breaking down ATP right through to adenosine, the Km values for adenine nucleotides are in the low millimolar range, raising doubts about the physiological significance of this enzyme in relation to nucleotide degradation.

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P2X RECEPTORS AND RENAL FUNCTION

When considering renal actions attributable to P2X receptors, it is important to remember that they are likely to work in conjunction with the numerous P2Y receptors present throughout the vasculature and renal epithelium. Moreover, the plasma membranes of any renal cell can contain a variety of P2 receptor subtypes and, in epithelial cells, the receptor population can be different in apical and basolateral domains. Although the assignment of a particular physiological response to a given P2 receptor has proven difficult, a number of approaches can be used to increase resolution. First, immunohistochemical techniques can identify the subtypes present in the region (and, if possible, the membrane domain) of interest. Second, pharmacological approaches can be used to stimulate or antagonize specific receptors in situ. However, at the time of writing, a truly selective agonist for any of the P2X subunits is lacking, although a few selective antagonists are available such as Ip5I (P2X1 antagonist) and A-740003 (P2X7 antagonist).10 Consequently, it is usually necessary to compare the individual responses to a variety of agonists to provide a pharmacological profile from which tentative conclusions can be drawn.

A complementary approach is to use ‘knockout’ mice in which the gene encoding the receptor of interest has been deleted. However, this is not without its own potential problems. Global deletion of a receptor subtype that performs a significant function is likely to lead to compensatory changes. The P2 receptor profile within the kidney may then change to restore overall excretion rates, which could then lead to misleading conclusions about the normal role of the receptor. The Cre-loxP system adds a degree of refinement to the gene-targeting approach, permitting tissue- or cell-type-specific deletion, but this has not yet been employed in renal P2 receptor research.

DISTRIBUTION OF P2X RECEPTORS IN THE KIDNEY

Vasculature

Figure 1(A) summarizes current knowledge about the distribution of P2X receptors in renal vascular and tubular structures in the rat. Immunohistochemical and Western analyses indicate that P2X1 receptors are present in the vascular smooth muscle of the rat renal, arcuate, and interlobular arteries and in the afferent, but not the efferent, arteriole.11 P2X2 subunits have been immunolocalized in the smooth muscle of larger arteries and veins within the kidney,11 and molecular evidence has recently been provided for P2X4 subunits, at least in arcuate and interlobular arteries.12 On the basis of mRNA detection and/or agonist pro-filing in cell culture systems, P2X2,3,4,5, and 7 subunits have been identified in glomerular mesangial cells, but of these, only low and variable expression of P2X7 immunoreactivity was found in the rat glomerulus.13

FIGURE 1 | P2X receptors in the rat kidney. (A) Localization. Only those receptors are shown for which firm evidence from immunohistochemical studies and/or Western blotting has been obtained. Where possible, apical (a), basolateral (b), or intracellular (intra) location is indicated. (B) Putative effects of P2X receptor stimulation on kidney function.

Tubule

Immunohistochemical studies have identified basolateral expression of P2X6 receptors in the rat PCT and apical expression of P2X5 receptors in the S3 segment of the pars recta; low-level expression of P2X4 protein was also seen in the PCT, though the membrane domain was not identifified.13

In the rat, thin descending and ascending limbs of Henle, there is some immunohistochemical evidence for P2X4 and P2X6 receptors (membrane domain not stated; Ref 13). The same applies to the TAL. In addition, a study of the rat TAL transcriptome found evidence for P2X3 as well as P2X4 receptors.14 Functional evidence for basolateral P2X receptors was provided by Jensen et al.,3 who showed in mouse mTAL that basolateral application of ATP caused an initial peak in [Ca2+]i followed by a sustained plateau; whereas the initial peak was attenuated in mTAL from P2Y2 knockout mice, the plateau phase persisted, suggesting the presence of an additional basolateral P2 receptor. Since the plateau phase was dependent on extracellular Ca2+, the authors proposed a Ca2+- permeable P2X receptor.3

In the distal nephron, immunohistochemical studies have identifified P2X4 and P2X6 receptors on the basolateral membrane of the rat distal tubule,13 and a wide range of P2X receptors has been identified in the CD. Immunohistochemistry has indicated the expression of P2X1 (sodium-restricted rats only; intercalated cells only), P2X2, P2X4, P2X5, and P2X6 subunits in CCD and medullary CD.13,15 With respect to membrane localization in principal cells, P2X4 and 6 were found in both apical and basolateral membranes; staining for P2X2 and 5 subunits were designated 'intracellular'.15 In the mouse, immunohistochemistry has localized P2X1 and P2X4 subunits to the apical membrane of medullary CD cells.16 Analysis of the human kidney transcriptome found that of tags for 258 genes conferring transport properties, the only P2X receptor detected in significant amounts in the CD was P2X4. 17

EFFECTS OF P2X RECEPTOR STIMULATION

The physiological effects of P2X receptor activation in the renal vasculature and in sections of the tubule are summarized in Figure 1(B).

Vasculature

Infusion of ATP into the renal artery alters renal vascular resistance, although the nature and magnitude of the response are dependent upon the basal vascular tone. Using the isolated perfused rat kidney preparation, the preglomerular arteries were found to be relatively insensitive to ATP, micromolar concentrations being required to evoke even transient vasoconstriction, whereas the afferent arteriole underwent sustained contraction at concentrations in the submicromolar range. The efferent arteriole was completely unresponsive to ATP.11 Thus, in this preparation, intrarenal administration of ATP is normally vasoconstrictive, owing to stimulation of P2X1 receptors. However, when baseline renal vascular resistance is high, ATP induces vasodilatation, due to P2Y-mediated production of nitric oxide (NO).11 The dominant receptor pool, as well as the source and local concentration of extracellular nucleotide, will therefore influence the net physiological response. ATP released from renal nerve terminals will act directly on the vascular smooth muscle, causing P2X1-mediated vasoconstriction, whereas the release of ATP in the vicinity of the endothelial P2Y receptors would be expected to promote NO synthesis and vasodilatation.

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Renal Autoregulation

Autoregulation of renal blood flow results from the combined influence of at least two mechanisms: the intrinsic myogenic response of the vascular smooth muscle and tubuloglomerular feedback (TGF). The myogenic response operates along the preglomerular vascular tree, responding to increased transmural pressure by channel-mediated calcium influx and consequent vasoconstriction of the vascular smooth muscle. The exact signaling mechanisms are not defined, but the local release of ATP is implicated. In the afferent arteriole, pressure-mediated vasoconstriction is markedly blunted by the P2 receptor antagonists PPADS or suramin or by the saturation and subsequent desensitization of the P2 receptor system. The central role of the P2 system is further underscored by experiments in P2X1-deficient mice, in which pressure-induced reductions in afferent arteriole diameter are abolished.11 This may be clinically significant since impaired P2X1 receptor function may underpin the decline in autoregulation associated with hypertension.18

TGF is a mechanism whereby changes in the concentration of NaCl in the fluid emerging from the loop of Henle (caused by changes in tubular fluid flow rate) elicit inverse changes in the glomerular filtration rate of the nephron of origin. TGF is mediated by the juxtaglomerular apparatus (JGA), which includes a sensor—the macula densa and an effector—the granular cells of the afferent arteriole; other components of the JGA (e.g., mesangial cells) also play a role.

Bell et al. demonstrated the release of ATP across the basolateral membrane of macula densa cells in response to increased luminal NaCl concentration within the physiological range, and the concentration of ATP in the cortical interstitium was shown to respond appropriately to inhibition or activation of TGF in vivo.6 This suggests that ATP is the primary signaling molecule for TGF, acting on P2X1 receptors. However, gene-targeting experiments indicate that ATP may not be the ultimate signal through which TGF causes constriction of the afferent arteriole; hydrolysis of ATP to adenosine appears to be critical. In vivo TGF responses are attenuated in mice lacking either adenosine A1 receptors or ecto-5'-nucleotidase, the enzyme catalyzing the fifinal stage of degradation of ATP to adenosine.11 Moreover, a recent in vivo study showed that intravenous infusion of ATP receptor antagonists had no effect on TGF.19

Tubule

Proximal Tubule

The major established effect of P2 receptor stimulation in the proximal tubule is the inhibition of sodium bicarbonate reabsorption as a consequence of the reduced activity of the apical Na+/H+ exchanger (NHE3). However, there is little doubt, on the basis of selective agonist/antagonist treatment, that this is mediated by apical P2Y1, rather than P2X, receptors.20 Other proximal tubular effects of P2 receptor stimulation include inhibition of phosphate reabsorption and stimulation of glucose uptake and of gluconeogenesis, but, again, P2Y receptors appear to be responsible. P2Y receptor domination in this segment has recently been challenged by a study in which the P2X receptor agonists α,βmeATP, and β,γ meATP were infused intravenously into anesthetized rats. Each agonist was natriuretic and increased lithium clearance (an index of end-proximal tubular fluid delivery) in the absence of a change in GFR; Na+K+ATPase activity in isolated proximal tubules was also inhibited.21 The P2 receptor subtype(s) responsible for this inhibitory effect on proximal tubular reabsorption could not be identifified.

Loop of Henle

The functional significance of P2 receptors in the thin limbs of Henle is still unclear, but a series of in vitro experiments by Garvin’s group has provided evidence for an effect of ATP in the TAL. In cell suspensions of rat mTAL, ATP increased intracellular NO production in a suramin-sensitive, concentration-dependent manner. On the basis that βγ meATP also caused an increase in NO production, it was argued that P2X receptors were primarily responsible, although it was noted that the P2Y2/4 agonist UTP also had a weak effect.22 The enzyme responsible for the NO production is NO synthase 3 (NOS3): ATP is unable to stimulate NO production in TAL cells from NOS3 knockout mice. NO (and, by implication, ATP) can reduce TAL transport by inhibiting apical NKCC-2 activity and (to a lesser extent) Na+/H+ exchange. ATP reduces TAL oxygen consumption dose-dependently and this is blocked by either suramin or millimolar doses of the NOS inhibitor L-NAME. The P2X agonist βγmeATP also reduces oxygen consumption, while the P2X antagonist NF023 blocks ATP’s action.22 Whilst this series of in vitro findings is strongly suggestive of a physiological role for P2X receptors in the control of TAL function, a full assessment awaits a comprehensive investigation of electrolyte transport in the loop of Henle in vivo.

Distal Tubule

No direct studies have been made in native distal tubules; consequently, our knowledge of the role of P2 receptors in these nephron segments is fragmentary and restricted to findings from studies of primary cultures of native cells or immortalized distal or ‘distallike’ cell lines. Activation of receptors characterized pharmacologically as P2X (membrane domain not stated) in an immortalized mouse distal convoluted tubule cell line has been shown to inhibit magnesium reabsorption. In addition, cultured cells from rabbit connecting tubules respond to extracellular ATP with an increase in [Ca2+] I and inhibition of sodium and calcium absorption. In this case, pharmacological profiling implicates P2Y2 receptors (on the basis of equipotency of ATP and UTP), but a contribution from P2X receptors cannot be ruled out.20

Collecting Duct

Extracellular nucleotides, acting from both apical and basolateral sides, can have significant effects on water and electrolyte handling in the CD—the fifinal site of regulation of the urinary output.

There is now overwhelming evidence that P2 receptor stimulation inhibits vasopressin-stimulated osmotic water permeability in the CD as a result of reduced intracellular levels of cAMP and increased intracellular PGE2. 23 On the basis of agonist profiling, the inhibition found in the rat was attributed to P2Y2 receptors, and gene deletion studies support this suggestion.24 Nevertheless, a recent study in a cultured, immortalized mouse CCD cell line (mpkC-CDc14) has provided evidence for the involvement of P2X receptors in the inhibitory effect on vasopressinmediated water reabsorption. Application of dDAVP to the basolateral membrane resulted in marked AQP2 immunofluorescence in the apical membrane, but when ATP was then added to the medium, either apically or basolaterally, the AQP2 was internalized.25 Treatment with dDAVP led to translocation of P2X2 and P2Y2 subtypes to the apical and basolateral membranes, respectively. When P2 receptors were coexpressed with AQP2 in Xenopus oocytes, activation of P2X2 and P2Y2 receptors (and also of P2Y4 receptors) reduced cell membrane AQP2 abundance and AQP2-mediated water permeability.25 These findings suggest that in addition to basolateral P2Y2 receptors, apically located P2X2 receptors can contribute to the downregulation of AQP2-stimulated water transport.

The effect of P2 receptor stimulation in the CD is not confined to water transport; a separate action is to inhibit ENaC-mediated sodium reabsorption. Studies in primary cultures and cell lines have consistently shown inhibition of amiloride- (or benzamil-) sensitive sodium transport. The P2 receptor subtype responsible has been variously ascribed to P2Y2 or P2X3 or 4. 20 As an exception to these findings, Li et al.16 reported an increase in short-circuit current following P2X1 and/or 4 stimulation in a mouse CD cell line (IMCD-3), although amiloride sensitivity was not tested. In native mouse CD, perfused in vitro, apical or basolateral ATP inhibits sodium reabsorption, an effect caused by decreased ENaC open probability. Pharmacological profiling and the use of genetically engineered mice point to a P2Y2-mediated effect.26 In contrast, an in vivo study in rats suggested that the inhibitory action of nucleotides on sodium reabsorption was a P2X-mediated effect.20 In this context, a patch-clamp investigation of split-open rat CCD has provided evidence that both apical P2X and P2Y receptors can affect ENaC activity.15 Activation of P2Y receptors (P2Y2 and/or P2Y4 subtypes) inhibited ENaC activity, whereas activation of P2X receptors, (P2X4 and/or P2X4/6 receptors), either inhibited or potentiated ENaC activity, depending on the luminal concentration of sodium. When luminal sodium was 50 mM (mimicking the normal physiological concentration), P2X4 and/or 4/6 activation potentiated ENaC activity, whereas when luminal sodium was high (145 mM), P2X4 and/or 4/6 activation inhibited ENaC activity. The net effect of these actions is strong inhibition of ENaC-mediated transport at high intraluminal sodium concentrations, and only mild inhibition at low intraluminal sodium concentrations (Figure 2).

FIGURE 2 | Proposed regulation of ENaC activity by P2X receptors in principal cells of rat collecting duct (CD). The hypothesis is that ENaC activity in the rat CD is differentially regulated by P2X4 and/or 4/6 receptors depending on the concentration of luminal Na+. A. When the concentration of luminal Na+ is normal (i.e., ∼50 mM), activation of apically expressed P2X4 and/or 4/6 receptors increases ENaC activity through the activation of PI3K. In contrast, activation of apically expressed P2Y receptors inhibits ENaC activity through the activation of PLC. N.B.The overall effect of P2 receptor activation (i.e.both P2X and P2Y, by using ATP) is a small degree of ENaC inhibition. B. When the concentration of luminal Na+ is high (i.e., 145 mM), activation of P2X4 and/or 4/6 receptors results in inhibition of ENaC activity by an unidentified mechanism, possibly involving an influx of Na+. As before, activation of apically expressed P2Y receptors inhibits ENaC activity through activation of PLC. The overall effect of P2 receptor activation (i.e., both P2X and P2Y, by using ATP) is a much larger degree of ENaC inhibition. (Reprinted with permission from Ref 15. Copyright 2008 American Society of Nephrology)

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P2X RECEPTORS IN RENAL PATHOPHYSIOLOGY

Polycystic Kidney Disease

Polycystic kidney disease (PKD) is associated with uncontrolled proliferation of renal epithelial cells and disordered fluid transport, causing the formation and expansion of fluid-filled cysts and subsequent destruction of the surrounding normal tissue. In culture, human PKD cells release more ATP than do normal proximal tubular cells, predominantly from their apical surface. ATP is concentrated in the cyst fluid, reflecting both increased ATP efflux and diminished ecto-ATPase activity.27 This extracellular ATP, acting on P2 receptors on cyst-lining cells, promotes both cell growth and fluid secretion. Furthermore, activation of P2X7 receptors may promote apoptosis and remodeling, permitting further cyst expansion. In support of this, P2X7 receptor protein expression has been reported in the cystic epithelium of the _cpk/cpk mouse model of autosomal recessive PKD. Using cells isolated from this model, the widely used P2X receptor agonist BzATP reduced cyst number, but not cyst size. In a rat model (Han-SPRD) of autosomal dominant PKD, increased mRNA for the P2X7 subtype was detected in cyst-lining cells, although similar increases in mRNA encoding other P2 receptors were also reported, suggesting a complex interplay of receptor subtypes in PKD.27

Renal Inflammation

In health, the renal expression of P2X7 receptors is extremely low but is increased markedly in a number of pathological conditions such as rodent models of diabetes mellitus and hypertension.27 Prolonged P2X7 receptor stimulation causes pore formation, leading to lysis and eventual cell death; P2X7 receptors can also mediate an inflammatory response through the release of cytokines such as IL-1β and IL-18.28 In a rodent model of proliferative glomerulonephritis, an increase in the glomerular expression of P2X7 is coincident with the onset of proteinuria. Moreover, P2X7 receptor gene knockout or treatment with a P2X7 receptor antagonist attenuates the disease severity.28 Finally, the potential role of the P2X7 receptor in renal fibrosis has been investigated in a mouse model of unilateral ureteric obstruction. Transient expression of P2X7 was detected in tubular epithelial cells following obstruction; and macrophage infiltration, fibrosis, and expression of TGF-β were all attenuated in P2X7 receptor knockout mice.28

In summary, although the details have yet to be established, it is clear that P2X receptors (in conjunction with P2Y receptors) have a significant role to play in the regulation of normal renal function, and also in a number of disease models. The way seems clear for the eventual use of interventions to modify these actions, thereby altering water and electrolyte excretion, as well as the treatment of specific renal pathological conditions.

ACKNOWLEDGMENTS

We dedicate this manuscript to the memory of our friend and colleague, David Shirley.

Work in the authors’ laboratories was supported by the Wellcome Trust, the Medical Research Council, the British Heart Foundation, St. Peter’s Trust for Kidney, Bladder & Prostate Research, and Kidney Research UK.

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