DUAL EFFECTS OF PROSTAGLANDIN E₂ ON SALT BALANCE AND BLOOD PRESSURE

Prosaglandin E₂ is the major prostanoid synthesized along the nephron⁸ and potently regulates the renal microcirculation^9,10 and salt and water transport¹¹, making inhibition of its synthesis an important candidate for mediating the renal side effects of NSAIDs. Like COX inhibitors, PGE₂ infusion may be either natriuretic or may promote Na⁺ retention and hypertension¹². Typically, PGE₂ is regarded as antihypertensive, and acute intrarenal PGE₂ infusion results in natriuresis and diuresis^13,14. NSAIDs are thought to release the kidney from the tonic natriuretic effects of endogenous PGE₂, resulting in Na⁺ retention and hypertension^3,15. It is thus surprising that chronic intrarenal PGE₂ infusion increases BP in conscious dogs¹⁶. The hypertension associated with chronic intrarenal PGE₂ infusion has been ascribed to direct stimulation of renal renin secretion^16,17. The observation that aspirin reduces BP and renin levels in renovascular hypertension patients is concordant with an important etiologic role for PGE₂-stimulated renin secretion in renovascular hypertension^5,6. In contrast, hypotensive effects of PGE₂ appear to predominate in patients with salt-sensitive essential hypertension, in whom NSAIDs exacerbate hypertension¹⁵. In these patients, NSAID-induced hypertension may result from the loss of tonic PGE₂-dependent natriuresis and dilation of resistance vessels¹². This article examines the evidence that these opposing effects of PGE₂ are mediated by distinct G-protein—coupled receptors (E prostanoid or EP receptors)¹⁸ resulting in altered renal Na⁺ excretion.

MULTIPLE PROSTAGLANDIN E₂ RECEPTORS

Prostaglandin E₂ was originally recognized as a potent vasodilator in both arterial and venous beds^19,20,21,22. This effect is mediated, in part, by direct relaxation of vascular smooth muscle, now thought to be coupled to increased cAMP generation^19,20. However, PGE₂ does not relax all smooth muscle beds uniformly, and it even constricts trachea, gastric fundus, and ileum²³. Importantly, structural analogs of PGE₂ that reproduce the dilator effects of PGE₂ are completely inactive in tissues where PGE₂ is a constrictor. Conversely, analogs that reproduce the constrictor effects of PGE₂ fail to affect tissues in which PGE₂ is a dilator²³. The differential effects of PGE₂ analogs were important initial evidence for the existence of multiple PGE₂ receptors¹⁸.

In a screen of compounds for antagonist activity, SC19220 was a selective EP antagonist, but only where PGE₂ was a smooth muscle constrictor²³. These receptors were originally designated EP₁, whereas SC19220-insensitive dilator effects were ascribed to a distinct receptor, designated EP₂. The differential sensitivity of tissues to several structural PGE analogs has led to the identification of at least four distinct EP receptors: the dilator receptors EP₂ and EP₄ and the constrictor receptors EP₁ and EP₃. The existence and molecular characterization of the four receptors have now been confirmed and characterized further by molecular cloning Table 1. Although the EP₁ receptor was originally classified by its smooth muscle constrictor effects and the EP₄ receptor by its vasodilator action, the consequences for Na⁺ balance and BP of activating renal EP₁ and EP₄ receptors may be quite different from the effects on smooth muscle.

Table 1 - E-prostanoid receptor pharmacology.

Full table (49K)

E-PROSTANOID RECEPTOR PHARMACOLOGY

The EP receptors are members of the G-protein—coupled family of receptors, possessing seven hydrophobic, membrane-spanning amino acid sequences²⁴. EP₁ receptors signal mainly via phosphatidylinositol biphosphate hydrolysis and couple to increased cell Ca^2+25,26,27. EP₁ receptors are distinguished by the availability of selective antagonists (such as, AH6809 and SC19220), which block activation Table 1. No absolutely selective EP₁ agonists have been reported. In contrast, vasodilator EP₂ and EP₄ receptors signal through increased cAMP^28,29,30. EP₂ receptors are activated selectively by butaprost, whereas high AH23848 concentrations block EP₄, but not EP₂, receptors^21,30. (The literature is somewhat confusing because prior to 1995, the cloned EP₄ receptor was categorized incorrectly as EP₂³¹.) EP₃ receptors inhibit cAMP generation via a pertussis toxin-sensitive, G_i-coupled mechanism and constrict smooth muscle^32,33. MB28767 and sulprostone are selective and potent EP₃ agonists but have variable activity at the EP₄ and EP₁ receptors, respectively. The EP₃ receptor is unique among the EP receptors in that numerous alternatively spliced variants exist, differing only in their carboxy-terminal tail^33,34,35. Importantly, these EP₃ splice variants couple differentially to alternate signaling mechanisms, including phosphatidylinositol biphosphate hydrolysis and increased cAMP (albeit at ligand concentrations typically 100- to 1000-fold greater than those required to inhibit cAMP generation via G_i)^35,36. Whether these signaling differences in EP₃ splice variants are physiologically relevant remains to be determined. The study of EP receptor physiology has been hampered significantly by the lack of receptor-selective agonists and antagonists. In this regard, the availability of mice with targeted disruption of specific EP receptor genes should prove an invaluable resource for evaluating the function of specific EP receptors^37,38.

PROSTAGLANDIN E₂ ACTION IN THE THICK ASCENDING LIMB

The multiplicity of EP receptors may underlie many of the complexities of PGE₂ action on salt and water transport along the nephron³⁹. In the intact animal, intrarenal PGE₂ infusion elicits natriuresis and diuresis without significant changes in glomerular filtration or renal blood flow, consistent with its inhibition of salt absorption along the nephron^13,14,16. This effect may reflect PGE₂'s well-demonstrated capacity to inhibit salt and water absorption in the thick ascending limb (TAL) and collecting duct (CD) directly^40,41,42,43. Stokes first demonstrated that PGE₂ directly inhibits Cl^- absorption in the rabbit medullary TAL (mTAL) from either luminal or basolateral surfaces⁴². PGE₂ was shown also to inhibit vasopressin- or calcitonin-stimulated cAMP generation in TAL^44,45. Because cAMP stimulates TAL transport, inhibition of cAMP generation by PGE₂ may explain PGE₂'s inhibitory effects on TAL transport⁴⁶. With EP₃-selective riboprobes, it has been shown that mRNA for the G_i-coupled EP₃ receptor is expressed in TAL, suggesting that it may mediate the observed inhibition of cAMP generation in this segment^47,48,49. Consistent with this, Good has demonstrated modulation of ion transport by PGE₂ in the rat TAL by a pertussis toxin-sensitive mechanism; however, these effects possibly also involve protein kinase C activation^43,50. Taken together, these data support a role for the EP₃ receptor in regulating TAL transport. This interpretation is complicated by the observation that, given alone, PGE₂, but not the EP₃ agonist sulprostone, also potently stimulates cortical TAL (cTAL, Tamm-Horsfall positive) cAMP generation^45,51. This suggests that a cAMP-coupled EP receptor (EP₂ or EP₄) might predominate in Tamm-Horsfall—positive cortical nephron segments, including cTAL or distal convoluted tubule⁵². If so, PGE₂-stimulated cAMP generation also could enhance NaCl absorption in these segments. A functional correlate for this possibility has yet not been established⁴².

MULTIPLE E-PROSTANOID RECEPTORS AND PROSTAGLANDIN E₂ EFFECTS ON TRANSPORT IN THE COLLECTING DUCT

In contrast to the mTAL and cTAL, PGE₂'s capacity to either increase or decrease cortical CD (CCD) water reabsorption and cAMP generation is well established. Added to vasopressin-stimulated CDs, PGE₂ potently inhibits water absorption⁴⁰, consistent with the classic diuretic effects of PGE₂ infusion^13,53. However, in the absence of vasopressin, basolateral PGE₂ actually increases osmotic water absorption^40,53,54. PGE₂ also simultaneously inhibits CCD Na⁺ absorption. Thus, at least three distinct transport effects of basolateral PGE₂ have been described: stimulation of basal water absorption, inhibition of vasopressin-stimulated water absorption, and inhibition of Na⁺⁺ absorption. Importantly, luminal PGE₂ also increases basal water absorption and transiently stimulates an amiloride-sensitive current, suggesting that urinary PGE₂ may also affect salt and water transport⁵⁴ Figure 1. As in smooth muscle, the distinct effects of PGE₂ in the CCD appear to be mediated by separate, coexpressed EP receptors^47,55.

Figure 1.

Cellular localization, signaling, and functional consequences of E-prostanoid (EP) receptor activation in the collecting duct. Abbreviations are: ATP, adenosine triphosphate; IP3, inositol triphosphate; PGE, prostaglandin E; PIP₂, phosphatidylinositol biphosphate; PKC, protein kinase C; PLC, phospholipase C.

Full figure and legend (109K)

The diverse effects of PGE₂ in the CD appear to be mediated by distinct signaling pathways^39,40,41. PGE₂ inhibits vasopressin-stimulated osmotic water absorption in the CCD via a pertussis toxin-sensitive process coupled to inhibition of cAMP generation, presumably via G_i^41,56,57. These functional data fit well with molecular studies localizing the EP₃ receptor to the CD and TAL (as described earlier here). In situ hybridization with EP₃-selective riboprobes shows high levels of EP₃ mRNA expression in human, rabbit, and mouse CD^47,48,55, a finding confirmed by reverse transcription-polymerase chain reaction on microdissected rat and mouse CD^49,58. Importantly, PGE₂-mediated inhibition of Na⁺ absorption is entirely unaffected by pertussis toxin⁴¹ but is rather Ca²⁺/protein kinase C dependent^41,59,60.

As opposed to EP₃-mediated inhibition of water absorption, evidence suggests that an EP₁ receptor initiates the Ca²⁺/protein kinase C-coupled inhibition of CCD Na⁺ absorption^40,41,61. The cloned mouse and human EP₁ receptors have been shown to signal via stimulation of inositol triphosphate generation and increased intracellular [Ca²⁺]^25,27. Interestingly, the tissue distribution of EP₁ receptor mRNA shows it is predominantly expressed in the kidney^25,62,63. PGE₂ increases intracellular Ca²⁺ in the CD, and maneuvers that prevent the Ca²⁺ increase completely block PGE₂-mediated inhibition of Na⁺ absorption⁴¹. Recently, two different EP₁ receptor antagonists, AH6809 and SC19220, have been shown to block both the PGE₂-stimulated Ca²⁺ increase and PGE₂'s capacity to inhibit Na⁺ absorption⁶¹. Finally, in situ hybridization shows that renal EP₁ receptor expression is localized exclusively in the CD^48,55,64. Together, these results strongly suggest that the EP₁ receptor stimulates Ca²⁺-coupled inhibition of CD Na⁺ transport.

The contribution of EP₁ receptor activation to PGE₂-mediated natriuresis remains uncertain. Although in vitro conditions allow the effective use of EP₁ receptor antagonists, the efficacy of the EP₁ antagonists in vivo has been severely limited by their poor solubility, binding to serum albumin, and their relatively low potency^23,65. Nevertheless, continued work toward the development of clinically active EP₁ receptor antagonists has been driven by evidence that the EP₁ receptor is important in PG-mediated pain and fever^66,67. It will be critical to determine whether EP₁ receptor antagonists have analgesic and antipyretic activity. As with NSAIDs, renal side effects of EP₁ antagonists may occur. If so, EP₁ receptor antagonists might reduce renal Na⁺ excretion and thereby result in hypertension.

Basolateral PGE₂ increases water absorption in the CD, apparently by stimulating basal cAMP production^40,54,60. EP₂ and EP₄ receptors signal via G_s-stimulated cAMP generation. EP₂ receptor mRNA is not detected in human kidney by in situ hybridization⁵⁵, and although EP₄ receptor mRNA is most notably expressed in the glomerulus, it is also detected in the epithelial cells of ureter and bladder, with less intense expression in the CD^29,55. The EP-selective analog (EP_2/3/4) 11-deoxy-PGE₁ stimulates cAMP generation in the CCD, whereas the EP_1/3-active analog sulprostone and the EP₂-selective analog butaprost are inactive^56,68. These data suggest that an EP₄ receptor mediates cAMP-stimulated water absorption in the CD. Interestingly, a similar EP receptor also appears to be present in the CD lumen⁵⁴. Activation of the luminal receptor occurs with PGE₂ and 11-deoxy-PGE₁, but not sulprostone, and increases basal water absorption and transiently hyperpolarizes the lumen negative voltage. Thus, urinary PGE₂ may modulate renal salt and water transport^54,69.

The possibility that PGE₂ enhances renal Na⁺ absorption via an EP₄ receptor is intriguing with respect to PGE₂'s contribution to certain forms of hypertension. Although NSAIDs typically reduce Na⁺ excretion in anesthetized animals, one intriguing study has shown a marked increase in urinary Na⁺ excretion, without any change in urine volume or renal hemodynamics, when meclofenamate or carprofen is administered to conscious dogs undergoing a water diuresis⁷⁰. This suggests that under these particular circumstances, endogenous PGs enhance Na⁺ absorption along the nephron. The capacity of PGE₂ to increase Na⁺ absorption in toad bladder has been known for more than 25 years⁷¹, so a similar capacity in renal epithelia is not surprising. It is of note in this regard that PGE₂ is thought to enter the urine in the loop of Henle and would thus have access to a cAMP-stimulating luminal EP receptor in distal nephron segments^72,73. The possibility that enhanced distal Na⁺ absorption contributes to PG-dependent, hyperreninemic renovascular hypertension⁶ remains unexplored.

E-PROSTANOID RECEPTORS AND RENIN RELEASE

Chronic intrarenal PGE₂ infusion produces hypertension that is accounted for primarily by increased renin release without an altered Na⁺ balance¹⁶. Because increased cAMP may mediate PGE₂-induced renin release, an EP₄ (or EP₂) receptor could also mediate increased renin release¹⁷. PGE₂ and PGI₂ can stimulate cAMP generation independently in isolated preglomerular renal arterioles Figure 2. Furthermore, cAMP directly stimulates renin release from cultured mouse juxtaglomerular apparatus (JGA) cells^17,74. Although localization of EP₂ or EP₄ receptors in the JGA has not been demonstrated, EP₄ receptor mRNA is expressed in the glomerulus^29,48,55. It is therefore conceivable that renal EP₄ receptor activation could increase BP both by enhancing renin release and increasing distal Na⁺ absorption. The latter might be mediated via effects in the cTAL, the CD, or both. This possibility is tempered by the fact that the precise mechanism by which PG_s contribute to renin release remains elusive, and in situ localization of EP receptors to the JGA has not been demonstrated. Rather, one report demonstrates EP₃ receptor mRNA is localized over the macula densa, suggesting this cAMP-inhibiting receptor may also contribute to the control of renin release⁴⁸.

Figure 2.

Intrarenal localization and consequences of E-prostanoid (EP) receptor activation along the nephron. Abbreviations are: cTAL, cortical thick ascending limb; CCD, cortical collecting duct; MCD, medullary collecting duct; mTAL, medullary thick ascending limb; PCT, proximal convoluted tubule; PGE₂, prostaglandin E₂; PST, proximal straight tubule;

Full figure and legend (96K)

In summary, EP₁, EP₃, and EP₄ receptors appear to coexist in individual nephron segments, including the TAL and CD Figure 2. EP₁ and EP₃ receptors may contribute to the natriuretic and diuretic action of PGE₂. In contrast, intrarenal EP₄ receptors may activate cAMP-stimulated salt and water absorption along the nephron. Finally, EP receptors also appear to play an important role in regulating renin release. These receptors may provide novel targets for modulating renal salt and water excretion as well as systemic BP. It seems likely that the present limited clinical utility of PG analogs will be transformed by the availability of truly receptor-selective antagonists.

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Acknowledgments

MDB is a recipient of a Veterans Administration Clinical Investigator career development award. Support for this project was also provided a Veterans administration merit award (MDB) and National Institutes of Health grants 2P01-DK38226, DK-37097 (MDB), and DK-46205 (RMB).

RLH was supported by funds from the Canadian MRC.