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Published in final edited form as: Curr Opin Pharmacol. 2015 Jan 20;21:82–88. doi: 10.1016/j.coph.2015.01.003

Regulation of Renal Function and Blood Pressure Control by P2 Purinoceptors in the Kidney

Justin P Van Beusecum 1, Edward W Inscho 1
PMCID: PMC5515225  NIHMSID: NIHMS654291  PMID: 25616035

Abstract

Kidneys are important regulators of extracellular fluid volume homeostasis. Extracellular fluid volume is a key regulatory component of long-term blood pressure control influenced by controlling tubular sodium transport. In recent decades, renal P2 purinoceptors (P2 receptors) have come to the forefront as a mechanism for regulating extracellular fluid volume. P2 receptors are broadly distributed in renal tubular and vascular elements where they confer segmental control of renal vascular resistance, autoregulation, and tubular reabsorption. Activation or impairment of renal P2 purinoceptors is implicated in the regulating blood pressure or causing renal pathologies including hypertension. In this brief review, we discuss the role of renal vascular and tubular P2 purinoceptors in the regulation of renal hemodynamics, maintenance of extracellular fluid volume, regulation of sodium reabsorption and the control of blood pressure.

Keywords: P2 purinoceptors, ATP, blood pressure regulation, pressure natriuresis/sodium reabsorption

Introduction

Normal healthy kidney function is an important element in the regulation of blood pressure. High blood pressure affects approximately 67 million American adults, or nearly 1 out of every 3 [1]. The risk for cardiovascular and renal disease doubles with every 20mmHg increase in systolic blood pressure [2]. With treatment of high blood pressure costing the nation approximately 48 billion dollars a year, regulation of blood pressure is critical from a clinical, economic and societal stand point [3].

Blood pressure regulation is a complex and integrated mechanism. In 1961, Guyton developed a computational model predicting how the kidney is the centerpoint of long-term blood pressure control. He stated that, “Long-term regulation of mean arterial pressure is controlled principally by the kidneys” [4]. In 1969, Guyton et al. went on to show the important mechanistic linkage between long-term blood pressure control and sodium excretion, which includes the “pressure natriuresis relationship” [5]. Guyton’s model described this relationship between renal perfusion pressure, sodium excretion and blood pressure as an important mechanism for regulating circulatory volume [6]. The kidneys regulate circulatory volume by controlling sodium and water balance, thus maintaining extracellular fluid volume (ECFV) homeostasis. Simply put, an increase in sodium and water consumption leads to an increase in ECFV, which in turn increases blood volume. This increases venous return to the heart, inducing atrial stretch and increases cardiac output, thus increasing systemic blood pressure [6]. When arterial pressure increases, the nephron reduces sodium and water reabsorption thus increasing sodium and water excretion, to return ECFV and blood pressure to normal; the so called “pressure natriuresis” phenomenon. Conversely, with a decrease in blood pressure, the nephron increases sodium and water reabsorption, to increase ECFV and thereby increase blood pressure.

In the last two decades, the importance of renal P2 purinoceptors (P2 receptors) has come to light by the realization that multiple P2 receptor subtypes are expressed along renal vascular and tubular structures. The importance of the renal P2 purinoceptor system may be of similar to that of the renin-angiotensin-aldosterone system or sympathetic nerve activity for the regulation of blood pressure and maintenance of cardiovascular health. P2 receptors are broadly distributed throughout the kidney where they control renal vascular resistance, autoregulation, and regulation of tubular reabsorption. In this brief review we will discuss recent findings on the roles of P2 receptors in regulating renal hemodynamics, maintenance of ECFV, sodium reabsorption and blood pressure control.

Renal P2 Receptor Expression

P2 receptors are activated by ATP and can be divided into two distinct receptor families designated P2X and P2Y. Currently there are seven P2X receptor subtypes (P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7) which function as ligand gated channels. Among many other roles, P2X receptors are important regulators of renal blood flow, vascular and endothelial function, tubular function, and inflammatory responses [7,8]. P2Y receptors are G-protein coupled receptors divided into approximately eight distinct subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14). Table 1 illustrates the distribution of P2X and P2Y receptors in renal vascular and tubular structures. Immunohistochemistry and western blot analyses indicate that P2X1,2,4,7 and P2Y1,2,4 receptors are found on arcuate, and interlobular arteries, as well as afferent arterioles [9–12•]. RT-PCR analysis and immunhistochemical staining reveals that P2Y1,2,4,6 receptors are found in isolated rat glomeruli [11,13]. Menzies et al. reported that P2X7 receptors are found in glomeruli [12•]. P2X4,5,6 and P2Y1,2,4,6 are located in the proximal tubule [8,11,14–16]. P2X and P2Y receptors have also been identified in the loop of Henle [8,11,14–18]. Messenger RNA and immunohistochemistry techniques reveal that P2X4,6 and P2Y1,2,4 receptors are expressed in the descending and ascending thin loops of Henle [8,11,14–21••]. Expression of P2X4,6 and P2Y1,2,4 receptors continues at low levels in the rat thick ascending limb [8,11,15,17•]. Marques et al. reported that P2X1,4,5 and P2Y2,6 receptors are expressed in the mouse thick ascending limb [22•]. P2X4,5,6 receptors are located on the basolateral membrane of the distal tubule [11,21••]. P2X1,2,4,5,6 are found in both the apical and basolateral membranes of the collecting duct epithelium [23]. Interestingly, there is only evidence for P2X4 receptor expression in human collecting duct cells [24]. P2Y1,2,4,6 receptors are also expressed in rat collecting duct as determined by immunostaining, protein expression and mRNA expression [16,23]. There is little information P2X3 and P2Y11–14 receptor expression in renal structures. Diverse P2 receptor expression in each nephron segment suggests that P2 receptors participate importantly in regulating solute and water reabsorption, which is essential for regulating ECFV and composition. Extracellular fluid balance is an important control point for regulating blood pressure and cardiovascular function.

Table 1.

Distribution of P2 receptors in the renal vascular and tubular structures.

P2 Receptor Segment
P2X1 vSMC[9,10,11,12], mTAL[22], CD[23]
P2X2 vSMC[10,11] CD[23]
P2X4 vSMC[11,12], PT[8,11], tDL[8,17], tAL[8], mTAL[8,17,21], DT[8,11], OMCD[23,24]
P2X5 PT[11], mTAL[22], DT[21], CCD[11,23], OMCD[11,23], IMCD[11,23]
P2X6 PT[8,11], tDL[8,11,17], tAL[8,11], mTAL[8,11,17], DT[8,11], CCD[23], OMCD[23], IMCD[23]
P2X7 vSMC[12], Glom[11,12]
P2Y1 vSMC[10,11], Glom[11,13], PT[11,16], tDL[21], mTAL[21], OMCD[16]
P2Y2 vSMC[10], Glom[11,13], PT[11,14,16], tDL[14,16], tAL[14,16], mTAL[14,22], cTAL[14], CD[14], CCD[14], IMCD[14,16], OMCD[14,16]
P2Y4 vSMC[9], Glom[11,13], PT[11,16], tAL[16], mTAL[21], CCD[23], OMCD[23], IMCD[23]
P2Y6 Glom[11,13], PT[15], mTAL[15,22], cTAL[15], CCD[15,23], OMCD[15,23], IMCD[23]
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CCD, cortical collecting duct; CD, collecting duct; cTAL, cortical thick ascending limb; DT, distal tubule; Glom, Glomerulus; IMCD, inner medullary collecting duct; mTAL, medullary thick ascending limb, OMCD, outer medullary collecting duct, PT, proximal tubule, tAL, thin ascending limb; tDL, thin descending limb; vSMC, vascular smooth muscle cell. There is little to no expression reported for P2X3 and P2Y11–14 receptor expression in the kidney.

Ecto-adenosinetriphophatases (Ecto-ATPase) are enzymes that are activated by either Ca2+ or Mg2+ and are able to hydrolyze nucleoside triphosphates (ATP, UTP) and nucleoside diphosphates (ADP, UDP) [25]. Sabolic et al. have shown that ecto-ATPases are found all along renal tubules, arterioles and peritubular capillaries [25]. These ecto-ATPases can metabolize ATP and other nucleotides and nucleosides that are released into tubular fluid or renal interstitial spaces and, in essence, provide a physiological “brake” to regulate endogenous P2 receptor-dependent signaling mechanisms. Consequently, the synergy between the tissue specific ATP-release and ATP catabolism yield a closely regulated method for controlling P2 receptor dependent mechanisms. Accordingly, this could represent a highly sensitive way of regulating renal tubular transport and renal hemodynamics, and thus contribute significantly to the control of extracellular fluid volume and blood pressure regulation.

P2 Receptor Function in the Renal Vasculature

Several studies have shown that P2X1 receptors are found on the afferent arteriole, while one study proposed that P2Y1 receptors are on both the afferent and efferent arterioles [11,20,26,27•]. P2X1 receptor activation regulates renal vascular resistance and confers autoregulatory control of renal blood flow, glomerular capillary pressure and thus glomerular filtration rate [28]. Using the juxtamedullary nephron preparation, Inscho et al. reported that P2X1 receptor blockade with NF279, blocked the pressure-mediated vasoconstriction when renal perfusion pressure was increased, consistent with an impaired autoregulatory response [29]. They also reported that afferent arteriole autoregulatory behavior was significantly blunted in P2X1 receptor knockout mice (P2X1−/−) compared with wild type controls [29]. Osmond et al. reported that whole kidney autoregulation of renal blood flow was impaired in rats treated with the P2X1 receptor antagonist, IP5I (Figure 1: Panel A) [28]. Whole kidney autoregulation of renal blood flow was unaltered during treatment with an A1 receptor antagonist, DPCPX (Figure 1: Panel B) [28]. These studies suggest that P2X1 receptors are important for afferent arteriole and whole kidney autoregulation. Recently, Schnermann et al. investigated the role of P2X receptors in mediating preglomerular resistance adjustments invoked by tubuloglomerular feedback signaling [30]. They reported that mouse tubuloglomerular feedback responses remained essentially normal during P2 receptor blockade suggesting that adenosine and P1 receptors may contribute to tubuloglomerular feedback induced vasoconstriction in vivo [30]. These studies suggest that there may be important differences in the roles of P1 and P2 receptors in regulating renal microvascular function. Menzies et al. reported that “selective” blockade of P2X7 receptors with Brilliant Blue G, reduced blood pressure and decreased renal vascular resistance, thus suggesting that P2X7 receptor activation may increase renal vascular resistance [12•,31••]. Consequently, impaired vascular P2 receptor activation may blunt renal autoregulatory control, permitting pathological increases in glomerular capillary pressure, leading to glomerular injury.

Figure 1.

Figure 1

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Percent change of baseline renal blood flow (RBF) in response to decreasing renal perfusion during P2X1 receptor antagonism. Percent change from baseline RBF in response to decrements in renal perfusion pressure with (open triangles) and without (closed circles) P2X1 receptor antagonism by IP5I. Panel B: percent change from baseline RBF in response to decrements in renal perfusion pressure with A1 receptor inhibition by DPCPX (open triangles) and during DMSO vehicle infusion (closed squares) and saline experiments (close circles). * P <0.05 vs. baseline. #P < 0.05 between saline vehicle. Figure modified from [27].

Activation of P2Y receptors in the renal vasculature can produce either vasoconstriction or vasodilation [32]. Studies using the juxtamedullary nephron preparation demonstrated that stimulation of either P2Y1 (2 methlythio-ATP) or P2Y2,4 receptors (UTP) vasoconstricts afferent arterioles [33]. Using isolated perfused kidneys, Eltze et al. showed that P2Y receptor agonists (ATP, ADP, UTP, ATPγS) induced vasodilation at low concentrations, and vasoconstriction at high concentrations [34]. This vasodilation elicited by “selective” P2Y receptor agonists seems to involve endothelial factors including nitric oxide (NO) or endothelium-derived relaxing factor, and is independent of prostaglandins [34]. Evidence for P2Y2 receptor dependent vasodilation has emerged from studies using P2Y2 receptor knockout mice (P2Y2−/−), which exhibited increased renal vascular resistance compared to wild-type controls [35]. This suggests that P2Y2 receptors exert basal vasodilatory influence on the renal vasculature. Furthermore, Rieg et al. showed that P2Y2 receptor activation decreases blood pressure in wild type mice and deletion of P2Y2 receptors (P2Y2−/−) increases systemic blood pressure [36]. These data show that P2Y receptors exert a vasodilatory influence that reduces systemic blood pressure. Therefore, P2X7 and P2Y2 receptors may provide novel therapeutic targets for regulating systemic blood pressure. Activation or impairment of renal vascular P2 receptors appear to play and important role in regulating renal vascular resistance, glomerular capillary pressure, and whole kidney autoregulation, therefore contributing to the regulation of renal function and systemic blood pressure.

P2 Receptor Activation in Renal Tubular Segments

Sodium balance and regulation of ECFV is controlled by regulating sodium transport along the nephron. An increase in systemic blood pressure increases renal perfusion pressure to the kidney. While autoregulation is efficient, it is not perfect, leading to a subtle increase in glomerular capillary pressure and a small increase in glomerular filtration rate which can increase tubular fluid flow rate, stimulate ATP release from tubular epithelium where it can activate P2 receptors and reduce epithelial sodium transport. Therefore, regulation of ECFV occurs in part by P2-receptor-mediated regulation of salt and water reabsorption by the nephron [37,38••].

Proximal Tubule

Activation of P2 receptors in renal tubules can inhibit renal sodium transport. P2Y receptors seem to predominate in the proximal tubule. Activation of P2Y2 receptors inhibits sodium and bicarbonate reabsorption by decreasing the activity of the Na+/H+ exchanger and Na+/K+ ATPase activity [39,40]. Microperfusion of P2Y1 receptor agonists in the proximal tubule lumen inhibit the Na+/H+ exchanger 3 in vivo and reduces Na+ reabsorption [41]. Increases in renal perfusion pressure cause a subtle increase in glomerular filtration rate thus increasing the filtered load received by the proximal tubule. This stimulates increased shear stress in the proximal tubule leading to local release of ATP and in turn activates proximal tubule P2Y receptors through autocrine/paracrine mechanisms. Activation of P2Y receptors reduces proximal tubule sodium reabsorption and enhances solute and water delivery to the distal nephron and contributes to the pressure natriuresis response to reduce ECFV and thus blood pressure (Figure 2: Panel A).

Figure 2.

Figure 2

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A summary of P2 receptor regulation of sodium transport throughout major segments of the nephron. Panel A (Proximal Tubule): Activation of apical P2Y1 and P2Y2 receptors by luminal ATP inhibits the activity of the Na+/H+ exchanger. P2Y2 receptor activation can also inhibit Na+/K+ ATPase in the basolateral membrane. Panel B (Medullary thick ascending limb): Basolateral P2X4 and apical P2Y2 receptor stimulation by ATP causes an increase in intracellular nitric oxide, that reduces sodium reabsorption through mechanisms of inhibiting the Na+/H+ exchanger, N+/K+/2Cl− co-transporter, and the Na+/K+ ATPase. Panel C (Distal Tubule): P2 receptors in the distal tubule cause both an inhibition and stimulation of epithelial sodium channel (ENaC) activity. Activation of basolateral and apical P2Y2 receptors reduces sodium transport through inhibition of ENaC activity. P2X4 receptor stimulation by ATP causes an increase in sodium reabsorption through mechanisms associated with ENaC channel activity. Panel D (Collecting Duct): P2 receptor activation by ATP causes a reduction or stimulation in sodium reabsorption in a collecting duct cell. Apical and basolateral P2Y2, and basolateral P2X4 receptor, at high levels of ATP, activity inhibits ENaC activity, reducing sodium transport. Low levels of ATP may stimulate ENaC activity through mechanisms linked to P2X4.

Loop of Henle

Increasing tubular fluid flow rate through the loop of Henle stimulates ATP release that activates P2 receptors in an autocrine/paracrine manner. Garvin et al. demonstrated that ATP and UTP increase intracellular nitric oxide (NO) production in cell suspensions of rat medullary thick ascending limb (mTAL) [42]. This ATP-mediated increase in NO production inhibits Na+/K+ ATPase and Na+/H+ exchanger activity in mTAL. Marques et al. reported that stimulation of P2X4 receptors increased intracellular NO, inhibiting the apical Na+/K+/2CL− (NKCC2) co-transporter [22•]. In a study using P2Y2−/− mice, Vallon’s group showed there is an increase NKCC2 co-transporter protein, suggesting an inhibitory role of P2Y2 receptors on sodium reabsorption and NKCC2 transporter expression in mouse mTAL [14,35]. These data suggest that increases in tubular fluid flow rate releases ATP that activates both basolateral and apical P2 receptors in the loop of Henle increasing intracellular NO production and reducing sodium reabsorption. The increase in glomerular filtration rate leads in an increase in tubular fluid flow rate from the proximal tubule that facilitates release of ATP from the tubular epithelium and the activation of P2 receptors in the loop of Henle. P2 receptor activation in this segment reduces sodium transport by the inhibition of Na+/K+ ATPase, Na+/H+ exchanger, and NKCC2 co-transporter, potentiating the pressure natriuresis response and decreasing blood pressure (Figure 2: Panel B).

Distal Tubule

Functional aspects of P2 receptors in the distal tubule have been limited to studies using cultured cell lines. A study by Zhang et al. has shown that addition of 2-methylthio-ATP, basolaterally to A6 (Xenopus kidney) cells stimulates epithelial sodium channel (ENaC) activity purportedly by P2X4 receptor activation, [43]. Extracellular ATP inhibited sodium and calcium absorption and increased intracellular Ca2+ concentration in cultured rabbit connecting tubule cells, likely by P2Y2 receptor activation [44]. These findings provide suggestion that P2 receptors in the distal tubule might regulate sodium transport via modulating ENaC activity in this segment (Figure 2: Panel C).

Collecting Duct

The rate limiting step in sodium reabsorption in the collecting duct is the apical expression of ENaC. ATP was first shown to inhibit ENaC in primary and immortalized mouse cell culture [45–47]. Work from Sipos et al. suggests that ATP release from collecting duct epithelium into the tubular fluid inhibits ENaC activity in the collecting duct, contributing to the pressure natriuretic response [48]. Patch clamp studies in isolated split open cortical collecting ducts of P2Y2−/− and WT mice showed that ATP reduces the open probability of ENaC via P2Y2 receptor activation [49]. Pochynyuk et al. also reported that P2Y2−/− mice developed salt-sensitive hypertension due to the lack of inhibition of ENaC [49]. Wildmann et al. reported that high extracellular sodium concentration levels (145 mM) evoked a P2X4 receptor mediated inhibition of ENaC in rat collecting duct, while low extracellular sodium concentration level (50 mM) increased ENaC activity [23]. P2X4−/− mice on a low Na+ diet had a lower mean arterial pressure compared to their WT littermates [50••]. Taken together, these data suggest that an increase in tubular fluid flow rate releases ATP into the tubular lumen, activating P2X and P2Y receptors in the collecting duct. Activation of P2 receptors inhibits or in some studies stimulates ENaC activity and sodium reabsorption, thus modulating urinary sodium excretion and regulating systemic blood pressure (Figure 2: Panel D).

Conclusion

P2 receptors are highly expressed in renal vascular, glomerular and tubular structures. Many studies have investigated the mechanisms by which P2 receptors contribute to the regulation of blood pressure control and overall kidney function. Activation of renal vascular P2 receptors contributes to the maintenance of a stable glomerular capillary pressure, and preservation of glomerular hemodynamics. P2 receptor activation in the nephron inhibits sodium reabsorption facilitating enhanced sodium excretion and contributes to the control of blood pressure. Certainly, the P2 receptor system represents an important renal tubular and vascular regulatory system that is tightly integrated into other neural, endocrine and cardiovascular mechanisms to regulate extracellular fluid volume and composition and thereby contribute to the regulation of body fluid homeostasis and blood pressure. Better understanding of the influence of P2 purinoceptors on renal vascular and tubular function will be important for clarifying their role in regulating renal hemodynamics and tubular transport mechanisms, and may lead to better therapeutic interventions for the treatment of hypertension.

Highlights.

  • Renal distribution of P2 purinoceptors in vascular, glomerular and tubular structures.

  • P2 receptors are important for renal autoregulation, and for regulation of renal and glomerular hemodynamics.

  • P2 receptors regulate tubular function, sodium reabsorption, extracellular fluid volume and blood pressure.

Acknowledgments

The authors would like to acknowledge grant support from National Institutes of Health (DK-44628, HL-098135, HL-095499) for EW Inscho and the American Heart Association pre-doctoral fellowship (14PRE20460061) for JP Van Beusecum.

Footnotes

Financial disclosure and conflict of interest statements: none.

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References and recommended reading

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