PGE2, Kidney Disease, and Cardiovascular Risk

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 PGE 2 in these events. This review summarizes the role of PGE 2 in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE 2 signaling in hypertension and diabetes, and outlines the contribution of PGE 2 to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE 2 could lead to new avenues to improve therapeutic options and disease management strategies. 27: 666-676, 201627: 666-676, . doi: 10.1681 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. PGE 2 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][4][5][6][7][8][9][10] PGE 2 binds four EP receptors (EP 1-4 ) to activate G protein signaling responses. Figure 1 illustrates the COX pathway leading to PGE 2 , as well as its target receptors. These receptors are often coexpressed in cells and usually have opposing effects (protective and harmful). PGE 2 acting on EP can alter vascular tone and influence renal blood flow and hemodynamics. 11-15 PGE 2 also stimulates the macula densa to activate the renin-angiotensin-aldosterone system, a key mediator of kidney injury. [16][17][18][19] Inflammatory, immune, and oxidative stress responses are influenced by PGE 2 , which are reported to alter growth, fibrosis, and apoptosis in renal cells. 20-26 PGE 2 also contributes to disturbances in collecting duct salt and water transport in polyuric diseases, 19,[27][28][29] and b cell defects in sodium and potassium handling associated with type I distal renal tubule acidosis. 30 PGE 2 /EP 4 also compensates for the loss of vasopressin V2 receptors in mouse diabetes insipidus. 28 Although attempts to block PGE 2 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/PGE 2 , while leaving the protective responses intact. EP 1 mediates many of the pathologic effects of PGE 2 in kidne...

Expression Profiling of Fibroblasts in Chronic and Acute Disease Models Reveals Novel Pathways in Kidney Fibrosis

“…Strikingly, TGF-b-cultured kidney fibroblasts suppress expression of multiple PG receptors making cells recalcitrant to PGE2 signaling. Given the proposed antifibrotic effects of PGE2, [14][15][16] these data suggest a novel mechanism for the regression of interstitial fibroblasts that is deregulated in a high-TGF-b environment.…”

“…PGs are lipid compounds with hormone-like activity, of which PGE2 has been implicated in tissue repair and ECM degradation. 15,16 Thus, PGE2 has been implicated as an antifibrotic factor. 5,14 We noted that one of its receptors, Ptger3, was down more than three-fold at FA3 and began to increase by FA7 and FA14, whereas the U14 samples remained low.…”

Lipidomic profiling of targeted oxylipins with ultra-performance liquid chromatography-tandem mass spectrometry

“…Alterations in oxylipin concentrations have been described for numerous diseases, including Alzheimer’s disease [20, 21], chronic pain [15, 22], diabetes [23], and cardiovascular disease [24]. Although these diseases are complex and multifactorial, they may share common pathological processes including neuroinflammation/inflammation [25], oxidative stress [2, 26], nociception [27], disrupted glucose metabolism [28, 29], and endothelial cell activation [30]. These processes consist of distinct biochemical cascades, but are closely intertwined with each other [27, 31–35].…”

Preexisting diabetes mellitus had no effect on the no-observed-adverse-effect-level of acetaminophen in rats

“…APAP and acetylsalicylic acid suppress the production of PGE2 via inhibition of COX activity (Gunaydin and Bilge, 2018). PGE2 may contribute to diabetes via EP3, a PGE2receptor, by inhibiting insulin secretion leading to impaired glucose tolerance and insulin sensitivity (Nasrallah et al, 2016). Taken together, the observed improvement in HbA1c and Glu levels may be caused by the PGE2 inhibitory function of APAP.…”