ono-ae1-329 and Disease-Models--Animal

With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.

Topics: Adipose Tissue; Animals; Cells, Cultured; Chemokines; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Inflammation; Insulin Resistance; Macrophage Activation; Macrophages; Male; Methyl Ethers; Mice; Mice, Inbred C57BL; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Prostaglandin E, EP4 Subtype; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction

Prostaglandin E(1) is frequently used for the clinical treatment of acute sensorineural hearing loss. However, the mechanisms underlying the effects of prostaglandin E(1) on the inner ear have not yet been elucidated. The physiological effects of prostaglandin E(1) are mediated by the prostanoid receptors prostaglandin I receptor and the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, the respective agonists for which have been purified. In the current study, we examined the efficacy of a local EP4 agonist application for the treatment of sensorineural hearing loss. We examined EP4 expression in the mouse cochlea using the reverse transcription-polymerase chain reaction and immunohistochemistry. The protective effects of local EP4 agonist treatment before or after noise exposure were tested in guinea pigs using measurements of auditory brain-stem responses and histological analysis. The results demonstrated EP4 expression in the cochlea, and showed that pre- and post-treatment with an EP4 agonist significantly attenuated threshold shifts of auditory brain stem responses, and significant attenuation in the loss of outer hair cells was found in local EP4 agonist treatment before noise exposure. These findings indicate that EP4 is involved in mechanisms for prostaglandin E(1) actions on the cochlea, and local EP4 agonist treatment could attenuate acute sensorineural hearing loss.

Topics: Alprostadil; Animals; Auditory Threshold; Cochlea; Disease Models, Animal; Evoked Potentials, Auditory, Brain Stem; Guinea Pigs; Hair Cells, Auditory; Hearing Loss, Noise-Induced; Hearing Loss, Sensorineural; Immunohistochemistry; Male; Methyl Ethers; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Noise; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; Reverse Transcriptase Polymerase Chain Reaction

Prostaglandin (PG) E2 is a potential anti-inflammatory mediator that attenuates airway inflammation. To elucidate the functions of the PGE2 receptors (EP1, EP2, EP3, and EP4) in allergic inflammation, we examined the in vivo effects of EP agonists on mucus hypersecretion and eosinophil infiltration in rat nasal epithelium.. We induced hypertrophic and metaplastic changes in goblet cells in nasal epithelium of ovalbumin-sensitized rats by intranasal challenge with ovalbumin. The effects of subcutaneous injections of EP agonists on mucus production and eosinophil infiltration were examined.. The EP4 agonist (1 to 100 microg/kg) dose-dependently inhibited ovalbumin-induced mucus production. The EP2 and EP3 agonists (100 microg/kg) also significantly inhibited mucus production. The EP3 agonist inhibited antigen-induced eosinophil infiltration, whereas the EP1 agonist showed no effect. This suppression of mucus production by the EP4 agonist was only effective when the EP4 agonist was given in the effector phase; administration in the induction phase resulted in no effect.. These results indicate that PGE2 acts as an anti-inflammatory mediator via the EP receptors of airways in allergic inflammation. Selective EP agonists may provide a new therapeutic strategy for airway mucus hypersecretion.

Topics: Alprostadil; Animals; Dinoprostone; Disease Models, Animal; Hypertrophy; Male; Metaplasia; Methyl Ethers; Mucus; Nasal Mucosa; Neutrophil Infiltration; Rats; Rats, Inbred F344; Receptors, Prostaglandin E; Rhinitis

X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present,no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. To develop what we believe to be the first viable animal model of XNDI, we generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen.Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin. Gene expression analysis suggested that activation of renal EP4 PGE2 receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology.These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of the newly generated V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI.

Topics: Animals; Aquaporin 2; Aquaporin 3; Diabetes Insipidus, Nephrogenic; Disease Models, Animal; Gene Deletion; Genetic Diseases, X-Linked; Kidney; Kidney Concentrating Ability; Kidney Tubules, Collecting; Male; Methyl Ethers; Mice; Mice, Knockout; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Vasopressin