Interplay between renal endothelin and purinergic signaling systems

Abstract

Alterations in extracellular fluid volume regulation and sodium balance may result in the development and maintenance of salt-dependent hypertension, a major risk factor for cardiovascular disease. Numerous pathways contribute to the regulation of sodium excretion and blood pressure, including endothelin and purinergic signaling. Increasing evidence suggests a link between purinergic receptor activation and endothelin production within the renal collecting duct as a means of promoting natriuresis. A better understanding of the relationship between these two systems, especially in regard to sodium homeostasis, will fill a significant knowledge gap and may provide novel antihypertensive treatment options. Therefore, this review focuses on the cross talk between endothelin and purinergic signaling as it relates to the renal regulation of sodium and blood pressure homeostasis.

since its discovery in 1988, the potent vasoactive peptide endothelin-1 (ET-1) has emerged as a fundamental regulator of sodium homeostasis and blood pressure (17). It accomplishes these physiological actions through two distinct receptors, ET_A and ET_B. Functional distribution of these receptors throughout the body determines the ultimate hemodynamic and renal tubular effects of ET-1 (25). ET_A receptors are primarily located on vascular smooth muscle cells and are responsible for the vasoconstrictor properties of ET-1. Activation of ET_A receptors is associated with renal hypertrophy, fibrosis, inflammation, and proteinuria (7, 9, 28, 29). ET_B receptors are located primarily on endothelial cells and collecting duct epithelial cells (17). Activation of ET_B receptors induces endothelium-dependent vasodilation in the vasculature and inhibits sodium and water reabsorption in the distal nephron (17). Increased renal tubular flow in response to high dietary sodium promotes inner medullary release of ET-1. This, in turn, facilitates sodium excretion mainly through ET_B receptor-mediated inhibition of epithelial sodium channel activity (ENaC) (4, 17, 30).

In recent decades, it has become clear that purinergic signaling is also important in regulating sodium balance and blood pressure (19, 32). ATP-binding purinoceptors (P2 receptors) are widely distributed in epithelial cells and vascular elements of the kidney (20). P2 receptors are classified as ionotropic P2X (P2X_1–7) or G protein-coupled P2Y (P2Y_{1,2,4,6,11–14}) based on their structure and signaling systems (5, 19). Autocrine or paracrine transduction of extracellular nucleotide signaling via P2 receptors is associated with a number of renal processes, which include tubular transport function. Specifically, increased sodium intake enhances luminal release of ATP, which activates P2 receptors and lowers the open probability of ENaC resulting in increased sodium excretion (33).

Therefore, renal P2 and ET receptors are important regulators of tubular sodium transport and extracellular fluid volume, key components in the long-term control of blood pressure. Genetic loss of either P2Y₂ or ET_B receptors has been implicated in the loss of blood pressure regulation in association with alterations in sodium and water handling (13, 24, 26, 31). Despite the similarities in the physiological effects of these two classes of receptors, the exact relation between these two systems in the kidney is not established yet. In this brief review, we discuss the potential link between renal purinergic and ET-1 signaling.

Purinergic Regulation of Renal Endothelin System

Recent evidence highlights a role for renal P2 receptors as regulators of ET-1 production. Pandit et al. (23) demonstrated that activation of P2 receptors, specifically P2Y₂ and P2X₇, increased ET-1 expression in inner medullary collecting duct cells. Our group has also shown that intramedullary infusion of the purinergic antagonist suramin attenuated ET-1-induced natriuresis, and combined blockade of ET_A and ET_B receptors inhibited the natriuretic response to medullary infusion of the P2Y_2/4 agonist UTP (14). This implies a possible role for P2Y₂ and P2Y₄ in regulating the production or release of ET-1 within the renal medulla (14). Cha et al. (6) observed that pretreatment of outer medullary collecting tubules with ATP inhibited ET-1-induced increase in intracellular calcium concentration (6), suggesting that ATP might prevent calcium mobilization by ET-1 signaling. Additionally, a recent study examining the development of renal fibrosis in response to overexpression of CD39, a key purinergic enzyme in the hydrolysis of ATP, revealed that increased CD39 activity enhanced the expression of ET-1 after unilateral ureteric obstruction (27). These findings support the hypothesis that P2 receptors are up stream of the ET-1 signaling cascade. Thus, ATP exerts significant effects on ET-1, indicating that activation of P2 receptors via ATP may regulate ET-1 release/production, which is particularly relevant in hypertension (Fig. 1).

Fig. 1.

Proposed mechanistic relationship between P2 receptors and ET-1 signaling on renal sodium handling in response to high-salt intake. Dashed line reflects our previously published data demonstrating a role for the ET_A receptor to increase urinary sodium excretion (U_NaV) in female rats (22), but the relation to P2 activation has yet to be resolved.

Extrarenal Purinergic and Endothelin System Interactions

The potential interaction between P2 and ET-1 signaling in the kidney is supported by previous evidence demonstrating a common dependency between these two systems in extrarenal tissues including cardiovascular (1, 2, 10, 12, 15, 16, 34, 36), nervous (3, 8), gastrointestinal (11), reproductive (6, 18, 21), and visual systems (34). Specifically, some studies have demonstrated that P2 signaling regulates ET-1 (1, 6, 15, 16, 34). Others suggest that P2 signaling was enhanced by ET-1 (3, 10–12, 18). Opposing to these findings, one study has shown that activation of P2 receptors blocked the effects of ET-1 (36).

Cardiovascular system.

Horckmans et al. (15) observed that loss of P2Y₂ receptors downregulated ET-1 expression and protected against myocardial infarction. Similarly, blockade of P2X_2/3 receptors inhibited the effects of ET-1 in vascular endothelial cells (16). In pancreatic arteries, activation of P2Y₁₄ induced vasoconstriction via elevation of intracellular calcium levels along with an increase in ET-1 production (1). Furthermore, P2 receptors may also be involved in the potentiating effects of ET-1 on the sympathetic response of cutaneous arteries (12). The purinergic antagonist PPADS prevented ET-1-induced intracellular calcium mobilization and partially attenuated ET-1-induced accumulation of total inositol trisphosphates in endothelial cells (34). These studies suggest that P2 and ET-1 pathways work cooperatively within the cardiovascular system. Nevertheless, ATP inhibited the cardiac hypertrophy induced by ET-1 in cardiac myocytes (36), suggesting that the interaction between purinergic and ET-1 signaling still remains inadequately defined.

Nervous system.

Barr et al. (3) showed that ET-1 increased neuronal sensitivity to ATP in sensory neurons, possibly due to sensitization of P2X₄ receptors. This mechanism was independent of the ET-1-driven rise in intracellular calcium (3). On the other hand, ATP completely blocked subsequent ET-1-evoked calcium responses in astrocytes (8), whereas ET-1 failed to desensitize the increase in intracellular calcium elicited by ATP, suggesting a dominant role of P2 receptors in modulating calcium signal of astrocytes.

Gastrointestinal system.

In duodenal epithelial cells, ATP release was increased in subepithelial fibroblasts treated with ET-1 (11). Additionally, ET-1 recovered the suppression in ATP release in response to raising cAMP levels (11).

Male reproductive system.

ET-1 potentiated the contractility of vas deferens via postjunctional mechanisms, which are mainly due to purinergic contractile responses (21). Moreover, ET-1 potentiated vas deferens contraction evoked by ATP and α, β-methylene ATP (18). These studies highlight that ET-1-induced facilitation of sympathetic neurotransmission in the vas deferens is due to potentiation of the postjunctional effects of the cotransmitter ATP acting at P2X receptors. Data also show that this potentiating effect is observed with ET-1 but not ET-3, suggesting an ET_A receptor-dependent mechanism (18).

Visual system.

Similar findings were reported in the visual system, where Vogler et al. (35) found that ET-1 inhibits osmotic swelling of rat retinal glial and bipolar cells by activation of growth factors and that this effect was associated with release of ATP and activation of P2Y₁ receptor. Collectively, these findings suggest a potential cooperative interaction between P2 and ET-1 signaling in different physiological functions.

Perspectives

Extracellular ATP and ET-1 are autocrine/paracrine agents that play important roles in renal tubular reabsorption of sodium and water. Recent evidence suggests these two signaling pathways are interdependent in the tubular elements of the kidney. Better understanding of the complexity of the interplay between P2 receptors and ET-1 signaling will help to understand the mechanism of blood pressure control and explore the therapeutic potential of new drugs for hypertension.

GRANTS

This work was supported by a postdoctoral grant from the American Heart Association (15POST25090329 to E. Y. Gohar), American Society of Nephrology (Ben J. Lipps Research Fellowship Program, Joseph A. Carlucci Research Fellowship to M. Kasztan), and by a grant from the National Heart Lung and Blood Institute (P01 HL095499 to D. M. Pollock).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s). E. Y. Gohar is also affiliated with Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.

AUTHOR CONTRIBUTIONS

E.Y.G. and M.K. prepared figures; E.Y.G. and M.K. drafted manuscript; E.Y.G., M.K., and D.M.P. edited and revised manuscript; E.Y.G., M.K., and D.M.P. approved final version of manuscript.