PGE₂, Kidney Disease, and Cardiovascular Risk: Beyond Hypertension and Diabetes

Abstract

An important measure of cardiovascular health is obtained by evaluating the global cardiovascular risk, which comprises a number of factors, including hypertension and type 2 diabetes, the leading causes of illness and death in the world, as well as the metabolic syndrome. Altered immunity, inflammation, and oxidative stress underlie many of the changes associated with cardiovascular disease, diabetes, and the metabolic syndrome, and recent efforts have begun to elucidate the contribution of PGE₂ in these events. This review summarizes the role of PGE₂ in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE₂ signaling in hypertension and diabetes, and outlines the contribution of PGE₂ to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE₂ could lead to new avenues to improve therapeutic options and disease management strategies.

Accelerated cardiovascular disease is the leading cause of mortality in patients with kidney disease.^1,2 This implies that kidney disease has a major effect on global cardiovascular risk, affecting fluid (volume, BP), electrolyte, and acid base balance, among many other cardiovascular risk factors. In fact, renal transplantation ameliorates cardiovascular risk, improves quality of life, and reduces mortality.² PGs are important homeostatic regulators of kidney function. PGE₂ is the major product of cyclooxygenase (COX)-2 and microsomal PGE synthase 1 (mPGES1), and both of these enzymes are elevated in renal diseases.^3–10 PGE₂ binds four EP receptors (EP_1–4) to activate G protein signaling responses. Figure 1 illustrates the COX pathway leading to PGE₂, as well as its target receptors. These receptors are often coexpressed in cells and usually have opposing effects (protective and harmful). PGE₂ acting on EP can alter vascular tone and influence renal blood flow and hemodynamics.^11–15 PGE₂ also stimulates the macula densa to activate the renin-angiotensin-aldosterone system, a key mediator of kidney injury.^16–19 Inflammatory, immune, and oxidative stress responses are influenced by PGE₂, which are reported to alter growth, fibrosis, and apoptosis in renal cells.^20–26 PGE₂ also contributes to disturbances in collecting duct salt and water transport in polyuric diseases,^19,27–29 and β cell defects in sodium and potassium handling associated with type I distal renal tubule acidosis.³⁰ PGE₂/EP₄ also compensates for the loss of vasopressin V2 receptors in mouse diabetes insipidus.²⁸ Although attempts to block PGE₂ using COX-2 or mPGES1 inhibitors have failed, selective inhibition of EP receptors may prove to be quite useful in controlling the deleterious effects of COX-2/mPGES1/PGE₂, while leaving the protective responses intact. EP₁ mediates many of the pathologic effects of PGE₂ in kidney diseases.²¹ In fact, a lack of EP₁ or EP₁ antagonism protects against hyperfiltration, albuminuria, and markers of injury in diabetic mouse models^21,26 or spontaneously hypertensive mice.³¹ Our group recently reported that EP₁ mediates reactive oxygen species and fibronectin induction in PGE₂ stimulated cultured mouse proximal tubules.²⁰ A protective role for EP₁ was described in glomerulonephritic mice³² but the reason for this discrepancy is unclear. EP₂ is mainly found in vascular and interstitial compartments of the kidney, and EP₂ knockout mice develop salt-sensitive hypertension.³³ The contribution of EP₂ to renal disease is unknown, but it may have a role in cyst formation in polycystic kidney disease.³⁴ EP₃ is mainly associated with water balance, mediating pathologic polyuria and tubular injury in postobstructive³⁵ and lithium-induced nephropathies^27,36 and diabetes insipidus.³⁷ Our group confirmed that EP₃ contributes to diabetic dysfunction and injury in mice, including hyperfiltration, hypertrophy, polyuria, and albuminuria (unpublished data). The protective nature of EP₄ was demonstrated in EP₄ null mice subjected to unilateral ureteral obstruction, with augmented fibrosis and inflammatory/fibrotic markers of injury.³⁸ PGE₂/EP₄ also maintains podocyte integrity and reduces the onset of proteinuria in diabetes,²³ and EP₄ agonism was beneficial in 5/6 nephrectomy.³⁹ EP₄ is also harmful in other studies; for instance, EP₄ antagonism prevented abnormalities in epithelial proliferation and chloride transport associated with autosomal dominant polycystic kidney disease.⁴⁰ In addition, EP₄ agonism promoted glomerulosclerosis and tubulointerstitial fibrosis in diabetes.⁴¹ Clearly targeting EP receptors may be advantageous in the treatment or prevention of kidney disease outcomes, but more work is needed to clarify the controversies and gain insight into the precise contribution of each receptor subtype. Figure 2 illustrates the contribution of PGE₂/EP to kidney disease processes (insufficiency and injury) that affect cardiovascular risk.

Figure 1.

PGE₂ synthesis and signaling pathways. AA is released by phospholipase A2 (PLA₂) from membrane phospholipids and converted into PGH₂ by COXs (COX-1/COX-2). COX activity is inhibited by NSAIDs. PGE₂ is produced by PGE synthase (mPGES-1, mPGES-2, and cPGES), and signals by binding to its G protein–coupled receptors EP₁– EP₄. Activation of EP₁ (coupled to G_q) increases intracellular Ca²⁺ via phospholipase C (PLC). Activation of EP₃ (coupled to G_i) increases intracellular Ca²⁺ via PLC and/or inhibits cAMP production via adenylate cyclase (AC). Activation of EP₂ or EP₄ (both coupled to G_s) stimulate cAMP production via AC. Activation of EP₄ also increases protein kinase B (AKT/PKB) via stimulation of phosphoinositide 3-kinase (PI3K). Arrowheads indicate stimulations, whereas blunt ends indicate inhibition.

Figure 2.

PGE₂ contributes to renal insufficiency and injury leading to increased cardiovascular (CV) risk. PGE₂ acting on EP₁, EP₃, and EP₄ contributes to renal disease processes causing insufficiency (hyperfiltration, altered water, and salt transport) and injury (albuminuria, growth/fibrosis, activation of renin-angiotensin-aldosterone). Overall, this may prevent or promote CV risk factors, including altered potassium homeostasis and pH balance as well as hypertension and edema. Hyperfiltration, albuminuria, and consequent loss of systemic oncotic pressure would lead to edema, and salt and water retention could be contributing factors. PGE₂ could affect sodium and water retention directly, or indirectly via activation of the renin-angiotensin-aldosterone system, which leads to volume expansion, hypertension, potassium loss, and hypokalemia. Mechanisms of pH balance are also dependent on renal transport properties. Renal growth and fibrosis are major factors that cause renal injury and contribute to renal insufficiency, thereby increasing the risk of developing CV disease.

PGE₂ in Hypertension and Diabetes

Inappropriate immune responses, chronic low-grade inflammation, and oxidative stress are important in the development and progression of target organ damage associated with both hypertension and diabetes.⁴² A comprehensive listing of the various systemic and metabolic factors involved (environmental/genetic, immune, sympathetic nervous system, and renin-angiotensin-aldosterone system), their complex interplay, and cardiovascular consequences that arise have been thoroughly reviewed.⁴³ Despite their obvious involvement, strategies to halt the mediators of these pathogenic mechanisms remain unsuccessful at managing disease progression. Because COX-2/mPGES1/PGE₂/EP receptors are implicated in many of the disturbances associated with diabetes and hypertension, many efforts are aimed at deciphering the exact role, to identify alternate targets for therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit COX, and mostly have hypertensive effects, especially with prolonged use (recently reviewed by Khatchadourian et al.⁴⁴). This response depends on the relative selectivity for each COX isoform, but both chronic high-dose ibuprofen (nonselective) and celecoxib (COX-2 inhibitor) increased systolic BP in diabetic mice.⁵ However, deoxycorticosterone acetate–salt hypertension was attenuated in mice lacking mPGES1, which otherwise displayed a 5-fold increase in PGE₂ levels.⁴⁵ The mechanisms were not fully explored but seem to be associated with oxidative stress responses in the kidney. PGE₂ is an important modulator of BP, acting at various levels (central and peripheral responses, renal hemodynamics, and salt and water balance). Yang and Du⁴⁶ provide an intricate overview of the PGE₂/EP pathways that act both centrally and peripherally to elicit hypertensive and hypotensive effects. We recently reviewed the role of renal PGE₂/EP receptors in the development of hypertension, affecting renal hemodynamics, renin release, and salt and water transport in the nephron.⁴⁷ Overall PGE₂ is an important antihypertensive agent under basal conditions, because of its potent diuretic and natriuretic roles in the kidney mediated by all four EP receptors⁴⁷ as well as its systemic depressor effect mediated by EP₂, which predominates in basal states.³³ In the absence of this depressor response, a pressor effect of EP₃ was revealed. EP₃ is also implicated in the central regulation of BP, stimulating sympathetic responses.⁴⁶ Moreover, pulmonary hypertension was attenuated in mice lacking EP₃ receptors.⁴⁸ It had long been recognized that prostacyclin analogs are beneficial in pulmonary hypertension, but their use is limited by the presence of vasoconstrictor EP₃. Accordingly, antagonizing EP₃ may prove useful in preventing vessel injury and remodeling in response to chronic hypoxia. Better control of PGE₂-mediated BP effects would be achieved by directly targeting EP-specific responses. In addition to conventional regulators of BP, new evidence of a more complex nature is emerging, with mechanisms involving the skin, the gut and mouth microbiome, and dietary nitrates in hypertension.^49–56 Future exploration of these avenues may unveil novel roles for PGE₂.

Hypertension is more prevalent in patients with diabetes, causing target organ damage, especially cardiovascular and renal vascular disease. The associated decline in cardiovascular health accounts for >80% of the mortality.^43,57 In addition to cardiovascular disease, the three major microvascular complications of diabetes are retinopathy, neuropathy, and nephropathy. The main trigger is hyperglycemia, with microvascular alterations contributing to progressive injury, but many vasoactive substances are also involved. PGE₂, as a major product of COX-2, clearly plays an important role in the end organ damage associated with diabetes. Diabetic retinopathy is the leading cause of blindness and has been associated with a number of injurious responses, with inflammation and oxidative stress as the main features.⁵⁸ COX-2 has long been implicated in the retinal damage associated with diabetes.^59–65 In the earliest stages of streptozotocin-induced diabetes in rodents, COX-2 and PGE₂ are elevated and COX-2 inhibitors reduce injurious responses to many pathogenic factors, like TNF-α⁶⁶ and vascular endothelial growth factor.^60,67 Although the mechanism appears to involve various second messengers (extracellular-regulated kinases, protein kinase A or C, NFκB), the nature of COX-2, PGE₂, and EP receptor involvement is poorly understood. A pilot study using the COX-2 inhibitor celecoxib to treat diabetic macular edema was inconclusive as a result of a small study group and short duration of the intervention.⁵⁸ A more elaborate trial is needed to ascertain the benefits of COX-2 inhibition in preventing blindness owing to macular edema in patients with diabetes. Interestingly, EP₃ has been implicated in ischemic retinopathy by inhibiting thrombospondin 1 and cluster of differentiation 36.⁶⁸ However, EP₂ protects against retinal ischemia reperfusion–induced angiogenesis by stimulating neuronal nitric oxide synthase and choline acetyltransferase,⁶⁹ whereas EP₄ promotes vascular endothelial growth factor–mediated neovascularization in cultured Müller cells.⁷⁰ A better characterization of the specific EP pathways would certainly yield better intervention possibilities in early diabetic retinopathy.

Diabetic neuropathy is another common microvascular complication of diabetes, consisting of progressive nerve dysfunction and damage due to altered blood supply, oxidative stress, and inflammatory injury. A wide range of symptoms arise as a result of the diabetic injury, ranging from an exaggerated perception of sensory stimuli to spontaneous paresthesias and pain, features of both allodynia and hyperalgesia. Recently published studies provide an elaborate review of the pathophysiology underlying the neuropathic pain⁷¹ as well as the detailed mechanisms triggered by hyperglycemia leading to nerve injury.⁷² Although hyperglycemia is central to the pathogenesis of diabetic neuropathy, a number of metabolic and vascular factors are involved. Most of the available therapies are symptomatic, including antidepressants, anticonvulsants, topical anesthetics, opioids, and other analgesics. NSAIDs have shown narrow therapeutic benefits,^73,74 but more work is needed to ascertain their benefits along with other pharmacological agents.⁷⁵ As a major inflammatory mediator in the diabetic milieu, COX-2 is implicated in diabetic neuropathy, and a more targeted approach to therapy will certainly prove more effective. Unlike nonselective NSAIDs,^76,77 COX-2 inhibitors show promise, with protection against nerve dysfunction and nerve fiber loss⁷⁸ as well as attenuated mechanical hyperalgesia⁷⁹ in experimental diabetes. There may be important considerations regarding therapy; for instance, mechanical allodynia was only prevented by inhibiting spinal COX-2 before established symptoms, otherwise the treatment becomes ineffective.⁸⁰ COX-2 is elevated in three diabetic rat models and may be implicated in tactile allodynia in the rat,⁶⁵ as well as p38-mediated allodynia in diabetic mice.⁸¹ A couple of studies in diabetic rodents indicate that both COX-2⁸² and PGE₂ are elevated in hyperalgesic conditions as well, and PGE₂ may mediate the bradykinin-induced nociceptor sensitization described in response to hyperglycemic hypoxia in diabetic rats.⁸³ Although PGE₂ can also modulate nondiabetic pain responses, contributing to heat- and acid-induced nociceptor sensitization,^84,85 more work in this area is warranted to better clarify the role of PGE₂/EP responses in diabetic neuropathy.

The best characterized role for COX-2 and PGE₂ is related to diabetic nephropathy, contributing to hyperfiltration, growth, fibrosis, apoptosis, and altered transport. A number of detailed reviews describe these events from hyperglycemia to altered renal function and kidney injury.^47,86–89 Both COX-2 and PGE₂ are consistently elevated in patients with diabetes and in a number of rodent models.^{5,7–10,21,90–97} Interestingly, despite the many claims that COX-2 mainly couples to mPGES1, a recent study reports that diabetic renal PGE₂ production by COX-2 is independent of mPGES1. In fact, diabetic mice lacking mPGES1 were no different than diabetic wild types with respect to albuminuria and other markers of injury. The authors suggest that another as-yet unidentified synthase may mediate PGE₂ production by the diabetic kidney.⁹⁵ Interestingly, in mice with type 2 diabetes, mPGES1 contributed to induction of glomerular PGE₂ synthesis, and the peroxisome proliferator–activated receptor-γ (PPAR-γ) agonist rosiglitazone protected against glomerular injury by targeting the mPGES1/PGE₂/EP₄ pathway. Unfortunately, glomerular COX-2 expression was not directly addressed in this study, but whole-kidney COX-2 was elevated in diabetic mice and was unaffected by rosiglitazone treatment.⁹⁷ COX-2 inhibitors may display some protection against diabetic injury, but studies are inconsistent.^5,90,92,94 As discussed above, a new interest has emerged in specifically targeting EP receptors to better control renal complications in diabetes. Diabetic kidney injury is ameliorated by EP₁ antagonism²⁶ and exacerbated by EP₄ agonism,⁴¹ but the role of EP₄ remains controversial. There is undoubtedly a detrimental role of PGE₂/EP receptors in diabetic nephropathy, but more work is needed to clarify the exact pathways involved, with many controversies awaiting clarification. Our group recently reviewed the role of each EP receptor in the diabetic changes as well as the potential of EP receptors as therapeutic targets,⁴⁷ suggesting that overall EP₁ antagonists and/or EP₃/EP₄ agonists may prevent renal injury (reducing growth/apoptosis, inflammation, oxidative stress, and fibrosis) and control kidney dysfunction (preventing hyperfiltration, renin secretion, and altered sodium and water transport) in diabetes. A detailed account is beyond the scope of this review.⁴⁷ However, we have new evidence that EP₃ contributes to diabetic dysfunction and injury in mice (unpublished data).

PGE₂ in Other Aspects of the Metabolic Syndrome

Obesity is a major factor in the assessment of global cardiovascular risk; like hypertension and diabetes, obesity is reaching epidemic proportions, especially in North America.⁹⁸ Abdominally distributed adiposity, as measured clinically by waist circumference, is a central component of the metabolic syndrome, both as a direct risk factor and as a contributor to other risk factors such as dyslipidemia, insulin insensitivity, glucose intolerance, and hypertension. The link between obesity and metabolic disturbances leading to diabetes, hypertension, and cardiovascular disease was thoroughly reviewed by Sowers.⁹⁹ The roles of leptin and insulin in controlling the adipose tissue browning process at the level of the hypothalamus were also recently reviewed.¹⁰⁰ A better appreciation of peripheral transformation of white-to-brown fat is of great interest, and PPAR-γ is a key regulator of adipose homeostasis, promoting differentiation of both white and brown adipocytes. A regulated coordination between mPGES-1 and PPAR-γ underlies white-to-brown transformations.¹⁰¹ COX-2 is also involved in the recruitment of brown adipocytes to white adipose tissue, but the nature of the PG involved was not identified.^102,103 PGE₂ is the main PG secreted by adipose tissue, and EP receptors are expressed in adipocytes, mediating its local responses.^104,105 EP₄ receptors in adipose tissue reduce chemokine production, by inhibiting IFN-γ and macrophage inflammatory protein 1α.¹⁰⁶ PGE₂/EP₃ increases both leptin secretion and lipolysis in rodent adipocytes, and it regulates adipogenesis.^107,108 Consistently, mice lacking EP₃ display enhanced night eating behaviors and are obese.¹⁰⁹ Moreover, PGE₂ regulates the transformation of white to beige fat, which protects against obesity and metabolic disease, but whether EP₃ is involved remains unclear.¹⁰¹ Although very little is known about all of the EP receptor pathways implicated, PGE₂ does inhibit adipogenesis via EP₄.¹¹⁰ It is also clear that mPGES-1/PGE₂ interact with PPAR-γ, promoting beige adipocyte differentiation in white adipose tissue, which increases energy expenditure and can prevent obesity related comorbidities. Interestingly, the treatment of obesity and related metabolic disturbances by targeting PG reductase-3 (which metabolizes the PPAR-γ ligand 15-keto-PGE₂) to limit PPAR-γ–mediated adipocyte differentiation, was reported.¹¹¹ 15-keto-PGE₂ is the product of PGE₂ oxidization; in chronic diseases characterized by a state of increased inflammation (increased COX2-PGE₂) and oxidative stress, this reveals a novel mechanism linking the two environments to regulation of adipogenesis. Therefore, targeting mPGES-1 or specific PGE₂ EP receptors may be important therapeutic avenues to explore in the treatment or prevention of obesity.

PGE₂ can also increase cardiovascular risk by contributing to atherogenesis. Since the introduction of COX-2 inhibitors into the clinical setting, prothrombotic and atherogenic consequences were discovered, mainly owing to the shifting synthesis of PGs to favor thromboxane and PGE₂ while reducing prostacyclin. This same PG profile was observed upon deletion of COX-2.¹¹² COX-2 null mice actually had the same phenotypic consequence as deletion of the prostacyclin IP receptor, with accelerated atherogenesis.^113,114 Instead, deletion of vascular mPGES1 limits the atherogenic response and prevents the thrombotic consequences associated with COX-2 selective antagonism.¹¹⁵ A central role was revealed for mPGES1 from myeloid cells to the atherogenic response in inflammatory states, suggesting that it can be targeted to protect against cardiovascular consequences.¹¹⁶ The role of COX-2 in the inflammatory response is controversial and it appears that timing is everything, with a dual role as a producer of proinflammatory and proresolving mediators in acute inflammation.¹¹⁷ PGE₂ plays a central role in the nonresolving inflammatory state associated with the formation of atherosclerotic lesions, and all three EP receptors are somehow implicated in the formation and stabilization of the atherosclerotic lesion. In fact, statins protect against thrombotic events by inhibiting COX-2/mPGES1/PGE₂/EP–mediated instability of carotid plaques, and the expression of EP₁, EP₃, and EP₄ receptors is reduced by atorvastatin in both the plaques and mononuclear cells of patients with carotid atherosclerosis.¹¹⁸ EP₃ is highly expressed in platelets and is involved in platelet activation¹¹⁹; EP₃ null mice displayed increased bleeding times and were less prone to developing thromboembolisms.¹²⁰ PGE₂ acting on EP₂ and EP₄ reduces human platelet hyper-reactivity, which is associated with increased cardiovascular risk,¹²¹ and was shown to inhibit mouse platelet aggregation.¹²²

PGE₂ also contributes to dyslipidemia and insulin resistance.^42,123,124 PGE₂ acting on EP₃ mainly has antilipolytic effects in adipose tissue of both obese and diabetic mice,^108,125,126 although mice lacking EP₃ are obese.¹⁰⁹ More work is needed to clarify this contradiction. Interestingly, in diet-induced obesity in rats, rather than PGE₂ from adipocytes, macrophage-derived PGE₂ via EP₃ signals adipocytes to reduce lipolysis, thereby contributing to abdominal adiposity and associated metabolic disturbances (insulin sensitivity, glucose intolerance, and cardiovascular abnormalities).¹²⁷ In this regard, PGE₂ also inhibits liver lipolysis, β-oxidation, and very low density lipoprotein synthesis further contributing to obesity,¹²⁸ yet the EP receptor is unknown. This lipid-accumulating effect of PGE₂ on hepatocyte lipid metabolism has been recognized for quite some time^129–134; however, it has also been demonstrated that PGE₂ derived from nonparenchymal liver cells attenuates insulin responses in the hepatocyte.¹²⁴ COX-2 derived PGE₂ also inhibits pancreatic insulin secretion, and COX-2 inhibitors and EP₃ antagonists improved β-cell function in mice, resulting in enhanced insulin release and glucose tolerance after a glucose challenge.¹³⁵ Kimple et al. also confirmed that EP₃ is elevated in the diabetic pancreas and reduces insulin secretion from diabetic islets.¹³⁶ Clearly, EP₃ receptors are involved in many deleterious responses associated with diabetes and the metabolic syndrome, and they prove to be enticing targets for therapeutic interventions. Figure 3 summarizes the contribution of PGE₂/EP receptors to hypertension and diabetes, while depicting the plethora of responses linking PGE₂ to cardiovascular risk. PGE₂ acting on EP receptors has been implicated in hypertension and diabetes, as well as many other aspects of the metabolic syndrome; as such, PGE₂ has a great effect on global cardiovascular risk.

Figure 3.

PGE₂ affects global cardiovascular risk by contributing to adipogenesis, hypertension, dyslipidemia, neuropathy, nephropathy, atherogenesis, diabetes, and retinopathy. Adipogenesis: PGE₂ stimulates leptin production via EP₃ contributing to adipogenesis. On the other hand, EP₄ inhibits IFN-γ and macrophage inflammatory protein 1α (MIP-1α) in adipocytes, preventing adipogenesis. PGE₂ promotes obesity by inhibiting lipolysis in the adipose tissue via EP₃. Hypertension: PGE₂ is a vasodilator via EP₂ and constrictor via EP₃. EP₃ can also upregulate TGF-β to promote vascular remodeling. Dyslipidemia: PGE₂ also inhibits lipolysis, β-oxidation, and very low density lipoprotein (VLDL) synthesis in the liver, but the nature of the EP receptor is unknown. Neuropathy: PGE₂ contributes to neuropathy via unknown EP receptors by promoting nerve dysfunction/fiber loss, allodynia (via p38), and hyperalgesia (via bradykinin). Nephropathy: PGE₂ contributes to renal injury and dysfunction via EP₁ and EP₃, whereas EP₄ prevents renal injury and dysfunction. Atherogenesis: PGE₂ also contributes to atherogenesis whereby EP₂ and EP₄ inhibit platelet hyperactivity and aggregation. On the contrary, EP₃ promotes platelet activation increasing the risk of thrombosis. Diabetes: PGE₂ can contribute to diabetes via EP₃ by inhibiting insulin secretion leading to impaired glucose tolerance and insulin sensitivity. Retinopathy: PGE₂ contributes to ocular ischemic injury via EP₂ by inhibiting neuronal nitric oxide synthase (nNOS) and choline acetyltransferase (ChAT). EP₃ contributes to ocular angiogenesis by inhibiting thrombospondin 1 (TSP-1) and CD36 (cluster of differentiation 36). EP₄ promotes ocular neovascularization by stimulating vascular endothelial growth factor (VEGF). Arrowheads indicate stimulations, whereas blunt ends indicate inhibition.

The global effect of hypertension, diabetes, and obesity epidemics is immeasurable. COX-2/mPGES1/PGE₂/EP receptors affect the global cardiovascular risk, including the development of hypertension, diabetes (retinopathy, neuropathy, and nephropathy), and other aspects of the metabolic syndrome (adipose homeostasis, dyslipidemia, and atherogenesis). PGE₂ is clearly implicated in glucose and lipid metabolism, vascular remodeling and injury, as well as nerve fiber dysfunction and injury. Because EP receptors are often coexpressed in the same cells and have opposing effects (protective and harmful), it is more promising to explore selective inhibition of EP receptors to modify disease processes. Although our knowledge of the harmful PGE₂ EP receptor pathways is expanding, more concerted research efforts are needed to determine the contribution of each EP receptor in these events. These strategies may prove to be quite useful in controlling the deleterious effects of COX-2/mPGES1/PGE₂, while leaving the protective EP receptor–mediated responses intact. A better understanding of the underlying mechanisms can lead to more targeted therapies to shrewdly manage disease outcomes.

Disclosures

None.