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American Journal of Hypertension logoLink to American Journal of Hypertension
. 2012 Oct;25(10):1042–1049. doi: 10.1038/ajh.2012.67

Distinct Roles of Central and Peripheral Prostaglandin E2 and EP Subtypes in Blood Pressure Regulation

Tianxin Yang 1,2,, Yaomin Du 3,
PMCID: PMC3578476  PMID: 22695507

Abstract

Prostaglandin E2 (PGE2) is a major prostanoid with a wide variety of biological activities. PGE2 can influence blood pressure (BP) both positively and negatively. In particular, centrally administered PGE2 induces hypertension whereas systemic administration of PGE2 produces a hypotensive effect. These physiologically opposing effects are generated by the existence of multiple EP receptors, namely EP1–4, which are G protein-coupled receptors with distinct signaling properties. This review highlights the distinct roles of PGE2 in BP regulation and the involvement of specific EP receptor subtypes.

American Journal of Hypertension, advance online publication 14 June 2012; doi:10.1038/ajh.2012.67

Keywords: blood pressure, brain, EP receptors, hypertension, kidney, mPGES-1, prostaglandin E2


Prostaglandins (PGs) are formed by a sequential series of three enzymatic reactions: release of arachidonic acid (AA) from membrane phospholipids by phospholipases, conversion of AA to an unstable endoperoxide intermediate PGH2 by cyclooxygenase (COX), and, finally, isomerization of PGH2 to bioactive prostanoids, including prostaglandin E2 (PGE2), prostacyclin (PGI2), Prostaglandin F (PGF), Prostaglandin D2 (PGD2), and thromboxane A2 (TXA2), by distinct terminal synthases. COX is best known as the molecular target of nonsteroidal anti-inflammatory drugs such as aspirin.1 These drugs have been used traditionally as analgesics for centuries and are some of the world's most widely used drugs. The seminal work by Sir John Vane delineated the mechanism by which aspirin exerts its anti-inflammatory, analgesic, and antipyretic actions.1 COX-2 exists in two isoforms, the constitutive COX-1 and the inducible COX-2; the two forms share 66% homology in amino acid sequence and similar enzymatic properties, but differ markedly with respect to cellular expression pattern and regulation.

Among terminal PG synthases, PGE synthase (PGES) specifically catalyzes the conversion of PGH2 to PGE2. To date, at least three major forms of PGES have been identified. They are designated membrane-associated PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES). mPGES-1 was cloned from human cells as microsomal glutathione S-transferase 1-like 1 (MGST1-L1) whose PGE synthesis activity was dependent on glutathione.2 mPGES-1 couples with COX-2 to mediate PGE2 production in response to inflammatory stimuli and mPGES-1 deletion blunts pain and inflammatory responses. The established role of mPGES-1 in the inflammatory response has prompted interest in development of mPGES-1 inhibitors as the next generation of analgesics.3,4 Besides inflammatory cells, mPGES-1 is constitutively expressed in a variety of tissues, including adipose tissues, stomach, spleen, and kidney. Increasing evidence suggests a potential role of this enzyme in regulation of sodium and water balance and vascular tone.59 A number of studies examine the effect of mPGES-1 deletion on angiotensin II (Ang II)-induced hypertension and yield variable results. mPGES-1−/− mice on a mixed background and an inbred C57/BL6 background develop accelerated hypertensive response to chronic Ang II infusion.7 However, another study using the same C57 background observes no impact of mPGES-1 deletion on the blood pressure (BP) response.10 Facemire et al. generated mPGES-1−/− mice on two inbred backgrounds, DBA/1lacJ and 129/SvEv.11 On the 129 background, BP was significantly higher in mPGES-1−/− mice than wild type controls at baseline and also during Ang II infusion. In contrast, on the DBA background, mPGES-1–/– mice have normal baseline BP and also similar hypertensive response to Ang II infusion as compared with wild type controls. The data clearly suggest that mPGES-1 modifies Ang II-induced hypertension depending on the genetic background. Along this line, mPGES-1 deletion impairs aldosterone escape12 and exacerbates the hypertensive response to deoxycorticosterone acetate-salt.6

mPGES-2 is a second mPGES that was originally purified from bovine heart and subsequently cloned. It is a 43-kDa protein containing a unique N-terminal hydrophobic domain, which determines the association with Golgi membrane; proteolysis leads to a mature, N-terminally truncated form of 33 kDa. A third enzyme is cPGES that was originally identified from rat brain as a cytosolic glutathione-dependent PGES. It is identical to p23, which is a steroid hormone receptor/hsp90-associated protein. Both mPGES-2 and cPGES possess PGES activity in vitro. However, neither mPGES-2 nor cPGES deletion results in a measurable decrease in PGE2 levels in tissues known to express these enzymes.1315 These findings do not support the contention that mPGES-2 or cPGES is a PGE2 synthase. Thus, it appears likely that mPGES-1 may represent the only enzymatic pathway capable of producing PGE2 in vivo.

The biologic action of PGE2 is mediated by G protein-coupled E-prostanoid receptors designated EP1, EP2, EP3, and EP4. These four subtypes of EP receptors couple to distinct signaling pathways. In general, the EP1 receptor signals via intracellular Ca2+ and phosphatidylinositol-bisphosphate hydrolysis, whereas the EP2 and EP4 receptors are coupled to Gs and signal by intracellular cAMP. The EP3 receptor is more complex in that it exists in multiple splice isoforms, which display differential coupling to distinct signaling mechanisms via Gi (inhibition of cAMP formation), Gs (stimulation of cAMP formation), and Gq (stimulation of intracellular Ca2+ release).16 In general, EP1/EP3 receptors are vasoconstrictive and prohypertensive whereas EP2/EP4 receptors are vasodilatory and antihypertensive.

Depressor Action of PGE2

General vasodilator action of PGE2

PGE2 is a potent vasodilator, although in some circumstances it can be a vasoconstrictor. At whole organism level, intravenous administration of PGE2 and PGE analogs produces a hypotensive effect. This effect is rapid and is observed within 20 s of drug infusion; it is also transient and mean arterial pressure recovers to baseline within 170 s after PGE2 administration.17 This short duration of action is due to the efficient metabolism of PGE2 in the venous blood of the lung. In many vascular preparations including rabbit saphenous vein, mouse aortic ring, hamster uterus, piglet saphenous vein, rabbit ductus arteriosus, human pulmonary vein, human middle cerebral artery, and rabbit ear artery, PGE2 directly relaxes the tissues preconstricted with KCl or norepinephrine, with a potency almost two orders of magnitude higher than that of the activation of PGI2 (IP) or PGD2 (DP) receptors.”1823 The vasodilatory action PGE2 is also observed in resistance vessels such as pig pial arterioles24 and canine renal juxtamedullary arterioles.25 However, in other vascular beds PGE2 induces vasoconstriction. In rings of human internal mammary arteries, which are frequently used for coronary artery bypass graft surgery, PGE2 induces vasoconstriction via EP3 receptors.26 This study suggests that EP3 antagonism may offer a new therapeutic intervention to increase vascular graft patency. In addition, PGE2 is shown to induce smooth muscle contraction in rat mesentery artery.27

Renal Action of PGE2

PGE2 regulation of renal hemodynamics

The status of the intrarenal circulation is an important determinant of body fluid and BP homeostasis. It is known that COX inhibiting nonsteroidal anti-inflammatory drugs do not produce major disturbances in renal blood flow and glomerular filtration rate at basal condition. However, under certain pathophysiological conditions, such as congestive heart failure, cirrhosis with ascites, and nephrotic syndrome, these drugs can cause a catastrophic decrease in glomerular filtration rate in these patients.2831 The vascular action of PGE2 intrarenally depends on the type of blood vessels with vasodilatory action in the preglomerular afferent arterioles, distal interlobular arteries, and medullary vasa recta but contrasting to little action in the postglomerular arterioles;32,33 in some instances, PGE2 causes vasoconstriction. The overall vasodilatory action of PGE2 may help sustain renal hemodynamic function under certain pathological conditions.

The microcirculation of the renal medulla plays a pivotal role in the long-term control of BP, although it represents only a small fraction of the total renal blood flow. For example, nitric oxide (NO) can exert a profound influence on BP control by modulation of renal medullary blood flow. The reduction of renal medullary blood flow by chronic intramedullary infusion of L-NAME leads to sodium retention and salt-sensitive hypertension.34 Conversely, the elevation of renal medullary blood flow by chronic intramedullary infusion of NO synthase (NOS) substrate L-arginine prevents the development of salt-sensitive hypertension in the Dahl salt-sensitive rat.3537 Emerging evidence suggests that PGE2, similarly to NO, may regulate renal medullary blood flow, thereby determining salt sensitivity. Chronic salt loading induces a marked increase in COX-2 expression in the rat medulla and chronic intramedullary infusion of COX-2 inhibitor leads to salt-sensitive hypertension.38 Further evidence supports PGE2 as an important mediator of the antihypertensive action of renal medullary COX-2. PGE2 attenuates the constriction in isolated perfused vasa recta preconstricted with endothelin or Ang II.39,40 In anesthetized uninephrectomized mice, acute intramedullary PGE2 infusion increases urine volume and urine sodium excretion.41 This natriuretic response is likely the result of increased renal medullary blood flow, although the contribution from the direct tubular effect is possible.

PGE2 regulation of tubular transport

Intravenous PGE2 administration to healthy dogs increases renal blood flow and induces a significant increase in urinary sodium excretion.42 When PGE2 and PGI2 were infused into the renal artery of dogs, both compounds elevated renal blood flow to a similar extent, but PGE2 induced a much larger increase in urinary sodium excretion than PGI2.43 These findings suggest that PGE2 may have a direct action on tubular function in addition to affecting renal hemodynamics. A significant number of microperfusion studies demonstrate that PGE2 directly inhibits NaCl reabsorption in the collecting duct (CD) and the thick ascending limb,44,45 although other investigators were unable to demonstrate an effect on the thick ascending limb or the CD in the similar setting.46 Most of these studies use the basolateral application of PGE2. Interestingly, luminal application of PGE2 produces a similar inhibitory effect on sodium transport in isolated perfused rabbit CD.47 This finding appears to be physiologically or pathologically relevant since PGE2 is present in the urine in nanomolar concentrations and its excretion is increased in the states of sodium loading and congestive heart failure.

PGE2 regulation of renal nerve activity

It is increasingly recognized that renal sympathetic nerve plays a pivotal role in fluid and BP homeostasis. Renal denervation reduces arterial pressure in various animal models of hypertension.48 More importantly, bilateral renal denervation in patients with resistant hypertension results in a long-term reduction in arterial pressure.49 In addition to a rich supply of sympathetic nerves, the kidney has abundant afferent sensory innervation, located primarily in the renal pelvic wall. A series of studies by Kopp et al. demonstrate that afferent renal nerve activity interacts with efferent renal sympathetic nerve activity, forming a feedback system termed the renorenal reflexes that have become an integrative part of the renal nerve circuit for the control of sodium balance and BP.5053 The functional interaction between the two types of nerve fibers is supported by the anatomic evidence that sympathetic efferent nerve fibers and afferent sensory nerve fibers often run separately but intertwined in the same nerve bundles in the renal pelvic wall. In a simplest form, the feedback system exists in such a way that increased efferent renal sympathetic nerve activity or increasing renal pelvic pressure leads activation of afferent renal nerve activity that in turn limits the increase of efferent renal sympathetic nerve activity so that efferent renal sympathetic nerve activity can be maintained at low level. PGE2 has been implicated to serve as an important activator of afferent renal nerve activity. Increasing renal pelvic pressure or bradykinin activates protein kinase C, which leads to increases in renal pelvic release of PGE2 via induction of COX-2. PGE2 activates the AC/cAMP/PKA transduction pathway, with a resultant increase in substance P release and increases in afferent renal nerve activity.54,55

Pressor Action of PGE2

Central PGE2 and sympathoactivation

In a sharp contrast to the above-described vasodilator and antihypertensive action of intravenously administered PGE2, centrally administered PGE2 via injection or infusion to the cerebral ventricles in anesthetized or awake rats elicits dramatic pressor responses accompanied by tachycardia, hyperthermia, and antidiuresis and causes increases in plasma norepinephrine and epinephrine, plasma renin activity (PRA), and plasma vasopressin (AVP).5660 Increasing evidence suggests that the hypertensive effect of central PGE2 is mediated by the sympathetic nervous system. In this regard, the pressor response is significantly attenuated by pretreatment with phenoxybenzamine and by cervical section of the spinal cord.58 In line with the changes in plasma catecholamines, recordings of splanchnic nerve activity demonstrate increased sympathetic neural firing following intracerebroventricular (ICV) PGE2.58 In contrast, a large body of evidence demonstrates that PGE1 and PGE2 inhibit the release of norepinephrine from sympathetic nerve endings and also suppresses the constrictor response of the effector cells to nerve stimulation, and may serve as a break against sympathoactivation in the peripheral tissues.61,62 Therefore, the E series of PGs can exert either positive or negative influence on sympathoactivation depending on the type of tissues.

In addition to the sympathetic nervous system activation, the increased AVP release may also contribute to the hypertensive effect of ICV PGE2. In the perfused ventriculo-cisternal system of anaesthetized dogs, PGE2 infusions elevate plasma AVP levels; in additional experiments, ICV injection of indomethacin decreased the plasma AVP concentration by ~50%.63 The observations that hypophysectomy and the AVP antagonist, d(CH2)5Tyr(Me) AVP both effectively attenuate the pressor response to ICV PGE2 suggest a role of AVP.59 Interestingly, the pressor response is completely abolished by the combination of the AVP antagonist and phenoxybenzamine, suggesting that the pressor effect of ICV PGE2 is the result of increased sympathetic nervous system activity and AVP release. The elevated PRA in response to ICV PGE2 may suggest the involvement of the renin–angiotensin system. However, pretreatment with captopril is without an effect, thus ruling out Ang II-dependent rise in BP.59

PGE2 and renin

PGE2 has been implicated to play a role in the pathogenesis of renin-dependent hypertension such as renovascular hypertension (RVH) by mediating the renin response to renal ischemia. Imanish et al. examined the effect of aspirin on BP in patients with unilateral RVH vs. those with essential hypertension.64 These investigators found that in patients with RVH, PGE2 concentration in the renal vein plasma from the stenotic kidney was elevated compared with the concentration from the normal kidney or in the aortic plasma; PRA was changed in parallel with the PGE2 levels. In contrast, PGE2 levels were similar between the left and right renal veins in patients with essential hypertension. Intravenous administration of aspirin lowered BP by 10 mm Hg, accompanied with parallel suppression of PGE2 and PRA levels at all sites in patients with RVH. Conversely, aspirin treatment did not improve, but deteriorate BP control in patients with essential hypertension.64

The above-mentioned clinical observations are supported by some animal studies demonstrating BP lowering effects of nonsteroidal anti-inflammatory drugs in rats with RVH. Indomethacin decreased BP and PRA in the rat model of RVH produced by complete ligation between the origin of renal arteries and it had no effect on BP when the left kidney was removed at the time of ligation.65 In two kidneys, one clip hypertensive (2K1C) rats, COX-2 was upregulated in both kidney, but to a greater extent in the clipped kidney.66 Moreover, COX-2 deletion or COX-2 inhibitors reduce renin secretion in response to maneuvers including low-salt intake, angiotensin-converting enzyme inhibition, angiotensin AT1 receptor antagonism, and reduced renal perfusion pressure.6772 However, functional studies using COX-2 inhibitors in 2K1C hypertensive rats have yield conflicting results. The selective COX-2 inhibitor SC58236 decreased renin production and release and lowered BP in RVH.73 In contrast, another selective COX-2 inhibitor celecoxib failed to affect BP or urinary aldosterone levels in this model despite the improvement of renal interstitial fibrosis.74

Among the five major prostanoids, PGE2, and PGI2 were shown to directly stimulate renin secretion in isolated juxtaglomerular cells through elevation of intracellular cAMP, the major signaling mediator of renin expression and secretion.71,72 Evidence is also available to support an in vivo role of PGE2 in regulation of renin secretion. In this regard, exogenous PGE2, when chronically infused to the dog kidney, induced increases in PRA and BP; the hypertension induced by intrarenal PGE2 infusion was renin-dependent since the BP was remarkably reduced by saralasin or an angiotensin-converting enzyme inhibitor.75

The characterization of mPGES-1 allows investigations of the role of endogenously produced PGE2 in renin regulation. Anatomic evidence is available to suggest colocalization of mPGES-1 with COX-2 in the cortical thick ascending limb and the macula densa, raising a possibility that mPGES-1 may functionally couple with COX-2 to produce PGE2 in the juxtaglomerular apparatus for regulation of renin secretion.76 Moreover, expression of macula densa mPGES-1, similarly to COX-2, was greatly increased in response to low-salt diet and angiotensin I-converting enzyme inhibition in rabbit kidneys.77 However, unlike COX-2 deletion, mPGES-1 deletion has failed to affect the renin response to furosemide, which is known to stimulate renin secretion via inhibition of Na+-K+-2Cl cotransporter type 2 in the macula densa.9 This observation argues against a functional role of mPGES-1 in renin regulation although more thorough investigations of this topic are apparently needed in the future studies.

In addition to renin regulation, abundant evidence demonstrates that PGE2 at nanomolar concentrations stimulates aldosterone release from cultured adrenal zona glomerulosa cells almost at the similar potency as Ang II.78 The stimulation of aldosterone release in response to PGE2 arises from the increased conversion of cholesterol to pregnenolone in the early step of aldosterone biosynthesis. The detailed signaling mechanism responsible for PGE2 regulation of aldosterone release is unclear, but appears to involve cAMP-mobilizing EP2 or EP4 receptors.78,79

Roles of EP1/EP3 Receptors in BP Regulation

The EP1 receptor was originally described as a smooth muscle constrictor.80 This receptor is generally coupled to an intracellular calcium signal, a common pathway leading to vasoconstriction by Ang II, endothelin-1, and TXA2. In some vascular beds, such as tail artery and mesenteric arteries, and cerebral arteries, concomitant activation of EP1 and EP3 receptors is responsible for PGE2-induced constriction via phosphatidylinositol pathway.8183 Consistent with the vasoconstrictive property, the EP1−/− mice exhibit a blunted pressor response to acute or chronic Ang II infusion.84 In this study, the effect of an EP1 selective antagonist SC51322 on hypertension was also tested in spontaneously hypertensive rats (SHR). The EP1 antagonism not only reduced BP in SHR but also blocked the acute pressor effect of the EP1/EP3 agonist sulprostone in mice.84 The consistent results obtained using genetic and pharmacological approaches demonstrate an overall prohypertensive role of the EP1 receptor. A recent study also suggests that activation of EP1 receptors is responsible for the increased vascular tone and the development of hypertension in db/db mice.85 However, the selective EP1 antagonist ONO-8713 failed to affect BP in stroke-prone spontaneously hypertensive rats (SHRSP) despite improvement of renal injury.86

Contrary to the above-described vasoconstrictive and prohypertensive action of EP1 receptors, the direct tubular action of EP1 receptor activation is natriuretic and therefore is antihypertensive. In isolated, perfused rabbit cortical CD, PGE2 inhibits sodium transport via elevated intracellular cytosolic calcium87 and this action is largely ascribed to activation of EP1 receptors.45 The physiological significance of natriuretic action of renal EP1 receptors in the context of the overall prohypertensive action of this subtype remains elusive.

Accumulating evidence suggests an important role played by EP3 receptor in mediating the sympathetic responses to central PGE2. Ariumi et al. examined the effects of ICV administration of PGE2 and selective agonists of EP1–4 receptors on central cardiovascular and renal sympathetic nerve activity. Among the four EP agonists tested, only ICV infusion of the EP3 agonist ONO-AE-248 resulted in an increase in RSNA with pressor and tachycardia responses, mimicking the effect of ICV PGE2 infusion.88 This observation has been extended by Zhang et al. who tested the effects of central administration of various EP antagonists in a similar experimental setting.89 PGE2-elicited cardiovascular and renal sympathoexcitatory responses were significantly reduced by pretreatment with the EP3 antagonist; the EP1 and EP4 antagonists had little or no effects. The independent studies respectively using EP agonists and antagonists consistently demonstrate that EP3 receptor is a dominant EP subtype responsible for the central sympathoexcitatory effect of PGE2. In a general agreement with this notion, EP3−/−mice show reduced brain injury after cerebral ischemia.90 Together, these results suggest that EP3 receptor activation may largely account for the pressor effect of central PGE2 via eliciting the sympathoexcitatory response and that EP3 inhibitors may hold promise to develop into novel therapies for the management of hypertension and stroke. Of note, the pressor action of EP3 receptors also occurs in peripheral vascular beds including rat mesentery artery, rat tail artery, guinea-pig aorta, human pulmonary artery, and murine renal vasculature.27,9194 The relative contribution of peripheral versus central action of EP3 receptors to increased BP is unclear.

Within the kidneys of rabbits and mice, EP3 receptors are abundantly detected in the renal medulla and localized to medullary thick ascending limb and the CD, the two important nephron sites for the natriuretic and diuretic actions of PGE2. Activation of EP3 receptors also inhibits AVP-induced cAMP accumulation. However, EP3 receptor deletion in mice does not produce a major influence on renal function or BP.92

Roles of EP2/EP4 Receptors in BP Regulation

The increase of intracellular cAMP through a Gs coupled pathway is a classical mechanism for vasorelaxation. EP2/EP4 receptors via this pathway have the potential to control vascular tone and BP. An important role of EP2 receptors in BP regulation is suggested by the hypertensive phenotype of EP2−/− mice at baseline and following a high-salt diet. While EP2−/− mice had a modest increase of BP at baseline, these animals developed profound hypertension when fed a high-salt diet. Moreover, the hypertension was quickly reversed by switching to normal salt diet and is re-established by resumption of the high-salt diet, establishing salt sensitivity.95 In light of the well recognized vasodepressor action of EP2 receptors, it is conceivable that the loss of this action may account for the hypertensive phenotype in EP2−/− mice. This notion is supported by the observation that in response to acute PGE2 infusion, EP2−/− mice developed hypertension rather than hypotension seen the wild-type mice. It is somewhat puzzling, however, that evidence from studies using the aortic ring preparation suggests a primary role of the EP4, but not the EP2 receptor in mediating PGE2-induced relaxations.21 Since conduit vessels were used in these preparations, a possibility still exists that EP2 receptor may be more important in resistance vessels. Recently, Chen et al. examined the role of EP2 in the natriuretic response to intramedullary infusion of PGE2 in mice.41 Intramedullary, PGE2 infusion to anesthetized, uninephrectomized mice produced natriuresis and diuresis, an effect that was recapitulated by intramedullary infusion of the EP2 agonist butaprost. Strikingly, the natriuresis was absent in EP2−/− mice.41 These results underscore an important role of the EP2 receptor in mediating the renal natriuretic action of PGE2. It is unknown whether the natriuretic effect of EP2 receptor activation is the result of altered renal medullary blood flow or tubular sodium transport.

As discussed above, in vitro evidence supports an essential role of EP4 receptors in mediating PGE2-elicited vasodilation in isolated aortic rings.21 The dilator action of EP4 receptor activation is dependent on endothelium derived NO production via increased eNOS activity as a result of dephosphorylation at Thr495. NO results in guanylyl cyclase-dependent accumulation of cGMP that leads to vasorelaxation in aortic rings. This study also presents in vivo evidence that the hypotensive response to acute PGE2 infusion is blunted in eNOS−/− mice. However, despite the well-defined vasodepressor action of EP4 receptors, the underlying signaling mechanism and the functional role of this subtype in long-term BP regulation in vivo remains unclear.

PGE2 Inactivation

The steady-state level of active prostanoids is determined by the relative rates of biosynthesis and inactivation. Thus, it is equally important to understand PG-degrading processes. PGs are rapidly cleared in a single passage through any of the vascular beds, including those of lung. This may serve as a key mechanism to ensure that PGs act in the vicinity of the site of synthesis, exerting autocrine, or paracrine functions. In this way, the local determination of the signal can prevent undesired action at a distance. Compared with the overwhelming information regarding the PG biosynthesis pathway, much less is known about the inactivation pathway. The inactivation of PGs has been proposed to involve two major steps: (i) selective uptake across plasma membrane via PG transporter (PGT) and (ii) oxidation inside the cell via NAD+-dependent 15-hydoxyprostaglandin dehydrogenase).9699 PGT is broadly expressed in many cell types with most abundant expression in the lung, suggesting that this transporter may be responsible for the single-pass metabolic clearance of PGs through that vascular bed in the lung. Recently, a structurally distinct PG-specific organic transporter (OAT-PG) in the OAT group of the SLC22 family has been identified.100,101 OAT-PG has high affinity and selectivity for PGE2, similar to PGT. Unlike PGT, however, OAT-PG is exclusively expressed in the kidney and further localized to the basolateral membrane of proximal tubules where 15-hydoxyprostaglandin dehydrogenase is expressed mostly in the cytosol.100 This anatomic evidence suggests functional coupling between transporters and metabolic enzymes in the clearance of extracellular PGs in the kidney.

Conclusion

PGE2 plays a diverse role in BP regulation depending on the site of action. Rodent studies demonstrated that centrally administered PGE2 elevates BP, but systemically administered PGE2 produces a hypotensive effect; PGE2 also modulates BP via affecting renin secretion. In most cases, the net effect of PGE2 is determined by the balance between the pressor action of EP1/EP3 receptors and the depressor action of EP2/EP4 receptors. The preferential activation of a particular EP subtype relies on the setting of BP regulation. For example, EP3 receptors play a dominant role in hypertension development induced by central PGE2 infusion through sympathoactivation whereas EP1 receptors mediate increased BP in response to Ang II infusion and in SHR via vasoconstriction. On the other hand, the EP2 receptor deficiency leads to salt-sensitive hypertension due to impaired renal natriuresis. An in-depth understanding of PGE2 signaling pathway will offer unique opportunity for development of novel antihypertensive interventions targeting specific EP receptors in a specific setting.

Acknowledgments

This work was supported by the National Basic Research Program of China 973 Program 2012CB517600 (No. 2012CB517602), the National Institute of Diabetes and Digestive and Kidney Diseases DK079162, and VA Merit Review. T.Y. is an Established Investigator from American Heart Association and Research Career Scientist in Department of Veterans Affairs.

Diclosure

The authors declared no conflict of interest.

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