Chronic kidney disease is a leading cause of morbidity and mortality in the world. A better understanding of disease mechanisms has been gained in recent years, but the current management strategies are ineffective at preventing disease progression. A widespread focus of research is placed on elucidating the specific processes implicated to find more effective therapeutic options. PGE2, acting on its four EP receptors, regulates many renal disease processes; thus EP receptors could prove to be important targets for kidney disease intervention strategies. This review summarizes the major pathogenic mechanisms contributing to initiation and progression of chronic kidney disease, emphasizing the role of hyperglycemia, hypertension, inflammation, and oxidative stress. We have long recognized the multifaceted role of PGs in both the initiation and progression of chronic kidney disease, yet studies are only now seriously contemplating specific EP receptors as targets for therapy. Given the plethora of renal complications attributed to PG involvement in the kidney, this review highlights these pathogenic events and emphasizes the PGE2 receptor targets as options available to complement current therapeutic strategies.

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...

Aims/hypothesis The first clinical manifestation of diabetes is polyuria. The prostaglandin E 2 (PGE 2 ) receptor EP 3 antagonises arginine vasopressin (AVP)-mediated water reabsorption and its expression is increased in the diabetic kidney. The purpose of this work was to study the contribution of EP 3 to diabetic polyuria and renal injury. -STZ mice also had increased protein expression of aquaporin-1, aquaporin-2, and urea transporter A1, and reduced urinary AVP excretion, but increased medullary V2 receptors. In vitro microperfusion studies indicated that Ep 3 −/− and WT-STZ CDs responded to AVP stimulation similarly to those of wild-type mice, with a 60% increase in fluid reabsorption. In WT non-injected and WT-STZ mice, EP 3 activation with sulprostone (PGE 2 analogue) abrogated AVP-mediated water reabsorption; this effect was absent in mice lacking EP 3 . A major finding of this work is that Ep 3 −/− -STZ mice showed blunted renal cyclooxygenase-2 protein expression, reduced renal hypertrophy, reduced hyperfiltration and reduced albuminuria, as well as diminished tubular dilation and nuclear cysts. Conclusions/interpretation Taken together, the data suggest that EP 3 contributes to diabetic polyuria by inhibiting expression of aquaporins and that it promotes renal injury during diabetes. EP 3 may prove to be a promising target for more selective management of diabetic kidney disease.

Renal prostaglandin (PG) E 2 regulates salt and water transport, and affects disease processes via EP 1-4 receptors, but its role in the proximal tubule (PT) is unknown. Our study investigates the effects of PGE 2 on mouse PT fluid reabsorption, and its role in growth, sodium transporter expression, fibrosis, and oxidative stress in a mouse PT cell line (MCT). To determine which PGE 2 EP receptors are expressed in MCT, qPCR for EP 1-4 was performed on cells stimulated for 24 h with PGE 2 or transforming growth factor beta (TGFβ), a known mediator of PT injury in kidney disease. EP 1 and EP 4 were detected in MCT, but EP 2 and EP 3 are not expressed. EP 1 was increased by PGE 2 and TGFβ, but EP 4 was unchanged. To confirm the involvement of EP 1 and EP 4 , sulprostone (SLP, EP 1/3 agonist), ONO8711 (EP 1 antagonist), and EP 1 and EP 4 siRNA were used. We first show that PGE 2 , SLP, and TGFβ reduced H 3 -thymidine and H 3 -leucine incorporation. The effects on cell-cycle regulators were examined by western blot. PGE 2 increased p27 via EP 1 and EP 4 , but TGFβ increased p21; PGE 2 -induced p27 was attenuated by TGFβ. PGE 2 and SLP reduced cyclinE, while TGFβ increased cyclinD1, an effect attenuated by PGE 2 administration. Na-K-ATPase α1 (NaK) was increased by PGE 2 via EP 1 and EP 4 . TGFβ had no effect on NaK. Additionally, PGE 2 and TGFβ increased fibronectin levels, reaching 12-fold upon co-stimulation. EP 1 siRNA abrogated PGE 2 -fibronectin. PGE 2 also increased ROS generation, and ONO-8711 blocked PGE 2 -ROS. Finally, PGE 2 significantly increased fluid reabsorption by 31 and 46% in isolated perfused mouse PT from C57BL/6 and FVB mice, respectively, and this was attenuated in FVB-EP 1 null mice. Altogether PGE 2 acting on EP 1 and EP 4 receptors may prove to be important mediators of PT injury, and salt and water transport. Prostaglandin (PG) E 2 is a major product of cyclooxygenase activity in the kidney. It has a substantial role in maintaining hemodynamics, salt and water homeostasis, and affects growth, inflammation, oxidative stress, and fibrotic responses (reviewed in refs. 1-3 ). Four EP receptors (EP 1-4 ) mediate the signalling responses to PGE 2 , by altering intracellular cAMP and/or Ca 2+ levels. Renal cells often simultaneously express multiple EP receptors, and their relative levels determine the cell's response. Although the contribution of the proximal tubule (PT) to overall renal prostaglandin synthesis is minimal, the role of PGE 2 in PT transport function has been considered. For instance, PGE 2 stimulates cAMP and activates protein kinase A, and in turn regulates basolateral organic anion uptake. 4,5 In contrast, long-term exposure to PGE 2 inhibits its excretion by decreasing the levels of basolateral organic anion transporters that are responsible for PGE 2 uptake in rat renal PT cells. 6 The underlying regulatory pathways are not completely understood, but short-term vs long-term exposure to PGE 2 has opposite effects on the overall cell response. PGE 2 also reduces phosphate transpo...

Hepatic encephalopathy (HE) is a major complication of cirrhosis, which is associated with gut microbial composition and functional alterations. Current treatments largely focus on gut microbiota using lactulose, rifaximin and other agents. However, despite these treatments, patients with HE have a high rate of readmission, morbidity and cognitive impairment. Fecal microbiota transplant (FMT) involves introduction of a donor microbiota into a recipient and is currently mainly used for recurrent C. difficile infection (rCDI). The role of FMT in cirrhosis and HE is evolving. There have been two randomized clinical trials (RCT) and several case reports/series in cirrhosis. Both RCTs were safety-focused phase 1 trials. One involved pre-FMT antibiotics and FMT enema versus standard of care, while the other involved 15 FMT capsules versus placebo without pre-FMT antibiotics. There was evidence of safety in both trials and the FMT group demonstrated reduction in hospitalizations compared to the non-FMT group. Changes in microbial function centered around short-chain fatty acids, bile acids and brain function showed improvement in the FMT groups. Long-term follow-up demonstrated continued safety and reduction in the antibiotic-resistance gene carriage. However, larger trials of FMT in HE are needed that can refine the dose, duration and route of FMT administration.