Urinary Prostaglandin E2 Levels Research Articles

Usefulness of Urinary Biomarkers for Assessing Bladder Condition and Histopathology in Patients with Interstitial Cystitis/Bladder Pain Syndrome.

This study investigated the usefulness of urinary biomarkers for assessing bladder condition and histopathology in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We retrospectively enrolled 315 patients (267 women and 48 men) diagnosed with IC/BPS and 30 controls. Data on clinical and urodynamic characteristics (visual analog scale (VAS) score and bladder capacity) and cystoscopic hydrodistention findings (Hunner’s lesion, glomerulation grade, and maximal bladder capacity (MBC)) were recorded. Urine samples were utilized to assay inflammatory, neurogenic, and oxidative stress biomarkers, including interleukin (IL)-8, C-X-C motif chemokine ligand 10 (CXCL10), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), eotaxin, IL-6, macrophage inflammatory protein 1 beta (MIP-1β), regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), 8-hydroxy-2′-deoxyguanosine (8-OHdG), and 8-isoproatane, and total antioxidant capacity. Further, specific histopathological findings were identified via bladder biopsy. The associations between urinary biomarker levels and bladder conditions and histopathological findings were evaluated. The results reveal that patients with IC/BPS had significantly higher urinary MCP-1, eotaxin, TNF-α, PGE2, 8-OHdG, and 8-isoprostane levels than controls. Patients with Hunner’s IC (HIC) had significantly higher IL-8, CXCL10, BDNF, eotaxin, IL-6, MIP-1β, and RANTES levels than those with non-Hunner’s IC (NHIC). Patients with NHIC who had an MBC of ≤760 mL had significantly high urinary CXCL10, MCP-1, eotaxin, IL-6, MIP-1β, RANTES, PGE2, and 8-isoprostane levels and total antioxidant capacity. Patients with NHIC who had a higher glomerulation grade had significantly high urinary MCP-1, IL-6, RANTES, 8-OHdG, and 8-isoprostane levels. A significant association was observed between urinary biomarkers and glomerulation grade, MBC, VAS score, and bladder sensation. However, bladder-specific histopathological findings were not well correlated with urinary biomarker levels. The urinary biomarker levels can be useful for identifying HIC and different NHIC subtypes. Higher urinary inflammatory and oxidative stress biomarker levels are associated with IC/BPS. Most urinary biomarkers are not correlated with specific bladder histopathological findings; nevertheless, they are more important in the assessment of bladder condition than bladder histopathology.

The association of urinary prostaglandins with uric acid in hyperuricemia patients

PurposeTo explore the association between uric acid and urinary prostaglandins in male patients with hyperuricemia.MethodsA total of 38 male patients with hyperuricemia in outpatients of Huadong Hospital from July 2018 to January 2020 were recruited. Serum uric acid (SUA), 24 h urinary uric acid excretion and other indicators were detected respectively. 10 ml urine was taken to determine prostaglandin prostaglandin D (PGD), prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), 6-keto-PGF1α, thromboxane A2 (TXA2) and thromboxane B2 (TXB2). Fraction of uric acid excretion (FEua) and uric acid clearance rate (Cua) were calculated. According to the mean value of FEua and Cua, patients were divided into two groups, respectively. The independent-samples t test and the Mann–Whitney U test were applied for normally and non-normally distributed data, respectively.ResultsAfter adjusting confounding factors (age, BMI, eGFR, TG, TC, HDL and LDL), SUA was negatively correlated with urinary PGE1(r = -0.615, P = 0.009) and PGE2(r = -0.824, P < 0.001). Compared with SUA1 group (SUA < 482.6 mg/dl), SUA2 (SUA ge 482.6 mg/dl) had lower urinary PGE1(P = 0.022) and PGE2(P = 0.019) levels. Cua was positively correlated with PGE2 (r = 0.436, P = 0.01). The correlation persisted after adjustment for age, BMI, eGFR, TG, TC, HDL and LDL by multiple linear regression analysis. In the Cua1 group (Cua < 4.869 mL /min/1.73 m2), PGE2 were lower than that in Cua2 (Cua ge 4.869 mL /min/1.73 m2) group (P = 0.011).ConclusionsIn male patients with hyperuricemia, SUA was negatively correlated with urinary PGE2, Cua was positively correlated with urinary PGE2. Urinary PGE2 were significantly different between different SUA and Cua groups.

Plasma renin, aldosterone, and urinary prostaglandin E2 levels in children with hypocalcemia due to vitamin D deficiency rickets

We investigated the effect of hypocalcemia on plasma renin, aldosterone, and urine PGE2 levels in children with vitamin D deficiency rickets (VDDR). In the study group, 25 patients with VDDR-induced hypocalcemia were treated with a single dose of 150,000–300,000 IU cholecalciferol and 50 mg/kg/day elemental Ca for 10 days. On any day between 21th and 30th days after the treatment, the patients’ clinical, biochemical and radiologic findings were re-evaluated. The healthy children with the same sex and similar age as the study group comprised the control group. Plasma sodium (Na), potassium (K), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH), 25- hydroxy vitamin D (25OHD), renin, aldosterone; and urinary Ca, creatinine (Cr) and prostaglandin E2 (PGE2) levels were measured in both the study (pre-treatment and post-treatment) and the control group. Plasma Ca, P, 25OHD and renin levels and urinary PGE2/Cr ratio in the post-treatment group were significantly higher than those in the pre-treatment group while K, ALP, and PTH concentrations were significantly lower. Plasma ALP and PTH levels in pre-treatment group were significantly higher than in the control group while Ca, P, 25OHD, aldosterone and renin concentrations and urinary PGE2/Cr ratio were significantly lower. Post-treatment plasma Ca level was significantly decreased in normal limits compared to the control group while other biochemical parameters were not different from the control group. Plasma Ca concentration was positively correlated with renin level and urinary PGE2/Cr ratio. The findings suggest that hypocalcemia may inhibit the production of renin, aldosterone and PGE2 and a blunt aldosterone secretion may develop even after recovery from hypocalcemia.

Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial

BackgroundPrimary hypertrophic osteoarthropathy (PHO) is a rare disease involving joint, bone and skin. Two underlying genes responsible for this disease—hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1)—are both associated with aberrant accumulation of prostaglandin E2 (PGE2). Cyclooxygenase-2 (COX-2) is a key enzyme in PGE2 synthesis. This study was intended to evaluate the safety and efficacy of COX-2 inhibitor in the treatment of PHO. MethodsWe recruited patients presenting to Peking Union Medical Hospital between January 2009 and December 2016 who were diagnosed with PHO. Participants were given the COX-2 inhibitor etoricoxib (60 mg once daily) and followed up for 9 months. Gene analysis was performed at baseline. The following data were collected at baseline and during treatment: visual analogue score (VAS), volume of the distal middle finger (VDMF), knee joint circumference (KJC), serum and urinary levels of prostaglandin E2 (PGE2) and PGE metabolite (PGE-M) and serum levels of inflammatory markers. ResultsA total of 27 patients were recruited, including seven patients with PHO type I (PHOAR1) carrying HPGD gene mutations and 20 patients with PHO type II (PHOAR2) carrying SLCO2A1 gene mutations. After treatment with etoricoxib, the majority of patients experienced resolution of symptoms including pachydermia (60.9%), joint swelling (100%), digital clubbing (74.1%) and hyperhidrosis (55.0%). In both the PHO subtypes, serum and urinary levels of PGE2 were elevated at baseline and declined sharply upon treatment. For PHOAR1 patients, serum and urinary PGE-M levels were relatively low and demonstrated minimal response to COX-2 inhibition. Among PHOAR2 patients, mean serum and urinary levels of PGE-M presented at a high level at baseline and were normalized after 3 months of treatment. No severe adverse effects were reported during the study period. ConclusionsWe found COX-2 inhibitor to be safe and effective for the treatment of PHO in our cohort. The translational potential of this articleThe underlying genes responsible for PHO suggest COX inhibitor as potential therapy, and our study demonstrates the efficacy and safety of this treatment.

Urinary biomarkers in patients with detrusor underactivity with and without bladder function recovery.

Detrusor underactivity (DU) is frequently encountered in elderly patients. Part of patients with DU might have bladder function recovery after treatment. This study investigated urinary proteins in these DU patients with and without bladder function recovery. A total of 37 patients with chronic urinary retention and urodynamically proven DU were enrolled. After treatment, 24 DU patients had bladder function recovery whereas 13 had not, after 1-year follow-up. Urine collection at baseline was performed, and the urinary protein including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and prostaglandin E2 (PGE2) were measured by ELISA. Twenty urodynamically normal, 34 detrusor overactivity (DO) and 15 detrusor hyperactivity and inadequate contractility (DHIC) patients served as comparative groups. Urinary NGF levels were significantly higher than normal in patients with DU (9.2±20.3 vs 1.85±2.9pg/ml, p=0.037). Urinary BDNF level was only significantly higher in patients with DU than that of the control group (153±199 vs 77.4±47.7pg/ml, p=0.033) but not in patients with DHIC or DO. Compared with the control group, the urinary BDNF level was significantly higher in DU patients with bladder function recovery (190±239pg/ml, p=0.033) but not in patients without recovery (85.8±43.7pg/ml, p=0.612). The PGE2 level was significantly higher than the control group in DU patients with bladder function recovery (1290±836pg/ml, p<0.0001) but not in patients without recovery (383±237pg/ml, p=0.130). Patients with DU and higher urinary PGE2 and BDNF levels might have a chance to recover bladder function than those with a lower protein level.

Urinary levels of prostaglandin E2 are positively correlated with intratumoral infiltration of Foxp3+ regulatory T cells in non-small cell lung cancer.

The immune microenvironment of primary tumors has been reported to be one of the factors influencing the prognosis of patients with cancer. The tumor-infiltrating regulatory T cell (Treg) count has previously been revealed to be positively correlated with intratumoral cyclooxygenase-2 (Cox-2) expression, and was also associated with poor survival among patients with non-small cell lung cancer (NSCLC). In addition, the urinary levels of a prostaglandin E2 (PGE2) metabolite (PGE-M) were used as a biomarker in clinical trials of the Cox-2 inhibitor celecoxib. In the current prospective study, the association of urinary PGE2 and PGE-M levels with intratumoral Cox-2 expression and Treg count was examined in patients with NSCLC. A total of 21 patients with NSCLC who underwent complete resection of the tumor at Kawasaki Medical School Hospital (Kurashiki, Japan) were enrolled. Urine specimens were obtained prior to surgery in order to examine urinary PGE2 and PGE-M levels. A significant positive association was observed between urinary PGE2 levels and the intratumoral Treg count (P=0.023), but not the intratumoral Cox-2 expression levels. No significant associations were identified between urinary PGE2 levels and any of the other clinicopathological characteristics examined, including age, sex, smoking history, histology, tumor size, nodal status and disease stage. However, no significant association was observed between urinary PGE-M levels and the intratumoral Treg count (P=0.069) or Cox-2 expression. In conclusion, urinary PGE2 levels were positively correlated with intratumoral Treg counts in patients with NSCLC in the current study. This indicates that urinary PGE2 may be an improved biomarker, compared with PGE-M, for the prediction of intratumoral Treg numbers.

Diuretic effect of extracts, fractions and two compounds 2α,3β,19α-trihydroxy-urs-12-en-28-oic acid and 5-hydroxy-3,6,7,8,4'-pentamethoxyflavone from Rubus rosaefolius Sm. (Rosaceae) leaves in rats.

Although diuretics have been widely used to treat hypertension along with others cardiovascular and renal disorders, no scientific data have been recorded to support the diuretic properties of Rubus rosaefolius Sm. (Rosaceae), a plant popularly used in Brazil to treat hypertension. Male Wistar rats were orally treated with: vehicle; hydrochlorothiazide; aqueous (AERR) and methanolic (MERR) extracts; dichloromethane (DCM), hexane (HEX) and ethyl acetate (EA) fractions; and the isolated compounds 2α,3β,19α-trihydroxy-urs-12-en-28-oic acid (TUA) and 5-hydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF). At the end of the experiment (after 8 or 24h), urine volume and other urine or plasma parameters were measured. AERR and MERR, at 100 and 30mg/kg, respectively, induced diuretic, natriuretic and kaliuretic effect. Additionally, the DCM and HEX, but not EA, at 10mg/kg, also increased urine volume and Na+ and K+ excretion. Both active constituents, TUA and PMF, at doses of 1 and 3mg/kg, showed an augmented diuretic and natriuretic index. While TUA revealed a kaliuretic action, PMF did not interfere with potassium excretion. The compounds increased urinary creatinine, but not urea, levels. TUA was able to decrease calcium excretion, as well as HCTZ, while PMF effect was associated with increased urinary prostaglandin E2 levels. The non-selective muscarinic receptor antagonist (atropine) prevented TUA-induced diuresis. In addition, indomethacin (a cyclooxygenase inhibitor) and atropine, exhibited the ability to block the diuretic effects prompted by PMF. Our study demonstrates the diuretic effect of extracts, fractions and two natural compounds obtained from R. rosaefolius leaves in rats.

Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: A randomized controlled trial.

The aim of the present study was to analyze the changes of plasma and urinary prostaglandin E2 (PGE2) levels in preterm infants with symptomatic patent ductus arteriosus (sPDA) treated with oral ibuprofen and acetaminophen. A total of 87 preterm infants with sPDA admitted to the Neonatal Ward of the Affiliated Xuzhou Hospital of Medical College of Southeast University from October, 2012 to June, 2015 were selected and randomly divided into the ibuprofen group (n=43, 10 mg/kg ibuprofen administered orally as initial dose, followed by 5 mg/kg during the first 24 and 48 h later) and acetaminophen group (n=44, 15 mg/kg acetaminophen administered orally once every 6 h for three days). The levels of plasma and urinary PGE2 in the two groups were estimated before and after treatment. The treatment of sPDA infants with ibuprofen (ibuprofen group) or acetaminophen (acetaminophen group) caused a significant decrease in the plasma and urinary PGE2 levels in comparison with plasma and urinary PGE2 levels before treatment (P<0.05). Furthermore, plasma and urinary PGE2 levels in the acetaminophen group (45.0±36.9 ng/l) were significantly lower than those in the ibuprofen group (73.5±44.8 ng/l, P=0.002). The arterial duct closure rate was similar between the acetaminophen [31 (70.5%)] and ibuprofen groups [33 (76.7%), P=0.506]. The incidence of oliguria was less among sPDA infants of the acetaminophen group [1 (2.3%)] than observed among the sPDA infants of the ibuprofen group [6 (14.0%)]; however, this difference was not statistically significant (P=0.108). Additionally, the incidences of fecal occult blood positive rate, intraventricular hemorrhage, neonatal necrotizing enterocolitis and bronchopulmonary dysplasia were distributed similarly in the ibuprofen and acetaminophen groups (P>0.05). The levels of platelet, serum creatinine and alanine transaminase showed no significant changes between the ibuprofen and acetaminophen groups (P>0.05). Following treatment with ibuprofen or acetaminophen, the extent of decrease of plasma and urinary PGE2 was significantly higher among sPDA infants with oliguria (135.0±38.0 ng/l) than that observed in sPDA infants without oliguria (52.5±37.0 ng/l) (P=0.01). The study also found a significant correlation between plasma and urinary PGE2 levels (r=0.648, P=0.01) and the coefficient of variation of urinary PGE2 (0.427) was less than that of plasma PGE2 (0.539). The clinical efficacy of oral ibuprofen and acetaminophen in the treatment of preterm infants with sPDA was similar with low adverse events, whereas acetaminophen-induced PGE2 levels were less than the levels observed in the ibuprofen-treated group. The incidence of oliguria was also lower in the acetaminophen group compared to the ibuprofen group. In addition, monitoring urinary PGE2 levels was more suitable because of its non-invasiveness in the clinical setting than monitoring of plasma PGE2 in preterm infants with sPDA.

A Common Mutation and a Novel Mutation in the HPGD Gene in Nine Patients with Primary Hypertrophic Osteoarthropathy.

Primary hypertrophic osteoarthropathy (PHO) is a hereditary bone disease characterized by digital clubbing, periostosis, and pachydermia. The HPGD gene encoding 15-prostaglandin dehydrogenase and SLCO2A1 encoding one type of prostaglandin transporter were found to be responsible for PHO. Mutations of either gene would lead to increased level of prostaglandin E2 (PGE2), which might contribute to the constellation of the symptoms. The aim of the study was to analyze the HPGD gene and the clinical characteristics in nine patients with the diagnosis of PHO. Nine patients, (eight males and one female) including two siblings and seven sporadic cases, were enrolled in the study. Clinical features were summarized, and blood and urine samples were collected. Sanger method was used to sequence the HPGD gene to detect mutations. Urinary PGE2 and prostaglandin metabolite (PGE-M) levels for each patient were measured and compared to the healthy controls. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). The levels of PGE2 in urine were much higher than normal in all patients, along with lower PGE-M levels. In conclusion, nine PHO patients were characterized by typical clinical manifestations including digital clubbing, periostosis, and pachydermia. A common mutation and a novel mutation in HPGD gene were identified to be responsible for the disease, and c.310_311delCT mutation is likely to be a hot-spot mutation site for Asian PHO patients.

Lithium‐induced NDI, Hypercalcemia and Urinary PGE2 Excretion Develop Independently in Mice

Lithium is the mainstay treatment for bipolar disorder. However, it leads to nephrogenic diabetes insipidus (NDI) and hypercalcemia in 10-20% of patients. Lithium-induced NDI is caused by the inability of the renal collecting duct to reabsorb water and correlates in C57BL/6 mice with the level of excreted prostaglandin E2 (PGE2). Lithium-induced hypercalcemia is ascribed to a decreased sensitivity of the parathyroid gland to blood Ca2+ levels. As lithium-induced NDI and hypercalcemia only occur in a subset of patients, we investigated whether these processes are linked by analyzing their development in 15 different inbred mouse strains. Starting at 10 weeks of age, female mice had access to normal chow or lithium diet (40mmol/kg). At day 8 and 26 mice were housed for 48 hours in metabolic cages to collect urine and at day 10 and 28 blood was isolated. Lithium treatment significantly elevated the urine production of several strains while other strains were not affected. Interestingly, in none of the strains lithium significantly affected urinary PGE2 levels. Furthermore, lithium did not significantly alter blood pH, while urinary proton excretion was elevated in several strains. Lithium-induced hypercalcemia was observed in 4 strains, and did not correlate with the effect of lithium on urine production. Our results demonstrate that development of lithium-induced NDI, hypercalcemia and excretion of PGE2 varies among inbred strains, indicating an independent development of these lithium-related features. Moreover, the diversity in response reveals that inclusion of additional strains may allow identification of susceptibility genes for these lithium-induced disorders.

The urinary levels of prostanoid metabolites predict acute kidney injury in heterogeneous adult Japanese ICU patients: a prospective observational study.

Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients. The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the urinary levels of prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1α), thromboxane A2 (TXA2) metabolite (11-dehydro-TXB2) were determined. Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6-OXO-PGF1α/Cr (r = 0.57, p < 0.0001) and 11-dehydro-TXB2/Cr (r = 0.47, p < 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE2/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF1α/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC-area under the curve (AUC): 0.75]. Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients.

Urinary VEGF and PGE2 levels and the association with arsenical metabolites in copper-smelting workers

ObjectivesTo examine vascular endothelial growth factor (VEGF) and PGE2 levels in urine from the copper smelting workers exposed to arsenic and analyse the relationships between urinary VEGF or PGE2 level...

Urinary nerve growth factor correlates with the severity of urgency and pain.

Urinary nerve-growth-factor (NGF) level reflected the severity of urgency in patients with lower urinary tract symptoms (LUTS) and pain in patients with Bladder pain syndrome/interstitial cystitis (BPS/IC). The aim of this study was to investigate the levels of biomarkers, nerve growth factor (NGF), and prostaglandin E2 (PGE2) among disease groups sharing similar urinary symptoms and to elucidate which symptoms are related to individual biomarker levels. We studied 83 patients with LUTS who visited our outpatient clinic from May 2011 to December 2012. On the basis of clinical symptoms and a 3-day voiding diary, patients were classified into three groups: those with frequency (n = 13), overactive bladder (OAB) (n = 35), and BPS/IC (n = 35). Patients with stress urinary incontinence (SUI) or microscopic hematuria served as controls (n = 24). Storage symptoms were evaluated based on OAB symptom score (OAB-SS). Mean patient age was 62.08 ± 11.47 (range, 23-84). Urinary NGF and creatinine-normalized NGF levels were significantly increased in those with OAB (201.90 and 4.08, respectively) and BPS/IC (173.71 and 2.72) compared with controls (77.77 and 1.29) and those with frequency (67.76 and 1.23). Neither value significantly differed between OAB and BPS/IC patients or between controls and frequency patients. Urinary PGE2 and creatinine-normalized PGE2 levels were not significantly different among groups. On linear regression analysis, urinary NGF levels were significantly correlated with urgency severity overall (R = 0.222) and also pain in BPS/IC patients (R = 0.409). The levels of urinary NGF were elevated in patients with OAB and BPS/IC but not those with frequency and reflected the severity of urgency. In BPS/IC patients, urinary NGF increased with pain severity.

Three novel mutations in the SLCO2A1 gene in two Chinese families with primary hypertrophic osteoarthropathy

Primary hypertrophic osteoarthropathy (PHO (MIM 167100)) is a rare genetic disease characterized by pachyderma, periostosis and digital clubbing. Mutations in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene and solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene have been demonstrated to be pathogenic causes. We aimed to identify the genetic cause of 2 unrelated patients with PHO. Urinary levels of prostaglandin E2 and prostaglandin E metabolite were measured in Proband 1 and his sister by competitive ELISAs. Mutation analysis of the HPGD and SLCO2A1 genes were conducted on both probands with PHO. Genomic DNAs of 100 healthy controls were isolated and subjected to polymerase chain reaction and direct DNA sequencing. The identified mutations were further confirmed in the parents of Proband 1. Protein modeling and data from PolyPhen-2 were used to evaluate the effects of novel missense mutations on protein SLCO2A1. The urinary levels of prostaglandin E2 and prostaglandin E metabolite in Proband 1 were much higher than those in unaffected individuals. Molecular genetic analysis revealed four SLCO2A1 mutations, including 3 novel ones (p.Arg603X, p.Gly183Arg and p.Asn534Lys) and a founder mutation, c.940+1G>A, in two probands with PHO. Missense mutations p.Gly183Arg and p.Asn534Lys, at highly conserved positions, were both predicted to be damaging. Protein modeling indicated that the mutation p.Gly183Arg altered the 3-dimensional structure of SLCO2A1. Three novel mutations within the SLCO2A1 gene have been demonstrated to be associated with Chinese PHO patients.

Mutations in theSLCO2A1Gene and Primary Hypertrophic Osteoarthropathy: A Clinical and Biochemical Characterization

We previously demonstrated that deficiency of the prostaglandin transporter (SLCO2A1) is a cause of primary hypertrophic osteoarthropathy (PHO). However, its clinical and metabolic characteristics have not been well defined. The objective of the study was to expand this mutational spectrum to better delineate the SLCO2A1 deficiency phenotype and investigate the clinical and metabolic characteristics of a cohort of subjects with PHO. Eleven affected individuals and their available healthy family members from 9 unrelated Chinese families with PHO (7 of which were previously undescribed) were clinically studied. The SLCO2A1 gene was screened and analyzed. Urinary levels of prostaglandin E₂ (PGE₂) and prostaglandin E metabolite (PGE-M) were measured using competitive ELISAs. The serum levels of total T, estradiol, sex hormone-binding protein, LH, FSH, and fasting gastrin were detected. Nine different SLCO2A1 mutations were identified in affected individuals in the 7 previously undescribed families, 7 of which (Glu165X, Ala286GlnfsX35, Gln356AlafsX77, Gly369Asp, Gly379Glu, Glu465Lys, and c.861+2T>C) were novel. The urinary levels of PGE₂ and PGE-M were much higher in the SLCO2A1-deficient individuals and decreased with age. There was no relationship between sex hormones and PGE₂ or PGE-M. There was no significant difference in the levels of fasting serum gastrin between PHO patients with watery diarrhea and their relatives. The present findings broaden the allelic spectrum of SLCO2A1 mutations. The urinary levels of PGE₂ and PGE-M in the SLCO2A1-deficient individuals decreased with age. The measurement of the excreted PGE₂ and PGE-M may have implications in the differential diagnosis, treatment, and follow-up of PHO.

Tumor necrosis factor-alpha induces renal cyclooxygenase-2 expression in response to hypercalcemia

The effect of tumor necrosis factor-alpha (TNF) on cyclooxygenase-2 (COX-2) expression in the renal outer medulla (OM) was determined in a model of dihydrotachysterol (DHT)-induced hypercalcemia. Increases in serum calcium and water intake were observed during ingestion of a DHT-containing diet in both wild type (WT) and TNF deficient mice (TNF−/−). Polyuria and a decrease in body weight were observed in response to DHT treatment in WT and TNF−/− mice. A transient elevation in urinary TNF was observed in WT mice treated with DHT. Moreover, increased urinary levels of prostaglandin E2 (PGE2) and a corresponding increase in COX-2 expression in the OM were observed in WT mice fed DHT. Increased COX-2 expression was not observed in TNF−/− mice fed DHT, and the characteristics of PGE2 synthesis were distinct from those in WT mice. This study demonstrates that COX-2 expression in the OM, secondary to hypercalemia, is TNF-dependent.

Effects of hypercholesterolemia on contrast media-induced nephrotoxicity in rats

To explore the effects of short- and long-term dietary hypercholesterolemia on contrast media-induced nephrotoxicity in rats. The male Wistar rats were fed either a normal rodent diet or a high cholesterol diet. At the end of 2 and 8 weeks, 8 rats from each group received a tail vein injection of either Iohexol injection (groups NC and HC) or vehicle (groups N and H). Blood lipid, renal function, renal hemodynamics, renal and urinary prostaglandin E2 (PGE2) and thromboxane B2 (TXB2), renal nitric oxide and malondialdehyde (MDA) were determined at Day 1 following the administration of contrast media. The dosing of contrast media induced obviously increased serum creatinine compared with normal rats ((185 ± 28) vs (53 ± 3) µmol/L, P < 0.01) and severe renal tubular necrosis in rats with a high cholesterol diet for 8 weeks but did not in normal-diet rats or rats with a high cholesterol diet for 2 weeks. The renal and urinary levels of PGE2 and TXB2 increased significantly in rats of groups H and HC at the end of 8 weeks. The renal production of nitric oxide decreased while the concentration of MDA increased markedly in groups HC and H at the end of 8 weeks. Long-term hypercholesterolemia appears to be a risk factor of contrast media-induced acute renal failure. And it may be associated with the disorder of intrarenal prostaglandins and the abnormality of renal nitric oxide system as induced by lipid peroxidation.

Cisplatin decreases renal cyclooxygenase-2 expression and activity in rats

Cisplatin (CP) induced acute renal failure (ARF) has previously been associated with decreased urinary prostaglandin E2 (PGE2) excretion and reduced aquaporin 2 (AQP2) expression in kidney collecting duct. In this study we examined the expression of cyclooxygenase (COX)-1 and -2 as well as AQP2 and the Na-K-2Cl cotransporter in kidneys from rats with CP induced ARF. Rats were treated with either CP or saline and followed for 5 days. Kidneys were dissected into three zones and prepared for immunoblotting, quantitative polymerase chain reaction (QPCR) and immunohistochemistry. Renal content and urinary PGE2 excretion was measured. Cisplatin treatment was associated with polyuria and a significant decreased creatinine clearance. Inner medullary PGE2 content and urinary PGE2 excretion was decreased in CP-treated rats. QPCR and semiquatitative immunoblotting demonstrated that CP treatment reduced COX-2, AQP2 and Na-K-2Cl cotransporter abundance in the different kidney zones, whereas no change in COX-1 was observed. Results were confirmed by immunohistochemistry. Cyclooxygenase-2 expression is decreased in inner medulla and cortex. Consistent with this urinary PGE2 levels were reduced. These data suggest that downregulation of COX-2 is responsible for impaired de novo generation of vasodilatory prostaglandins which may play an important role for the CP induced renal vasoconstriction and development of nephropathy.

791 CHRONIC HYPERLIPIDEMIA CAUSES DETRUSOR OVERACTIVITY AND INCREASE IN URINARY PROSTAGLANDIN E2 RELEASE IN RABBITS

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research1 Apr 2011791 CHRONIC HYPERLIPIDEMIA CAUSES DETRUSOR OVERACTIVITY AND INCREASE IN URINARY PROSTAGLANDIN E2 RELEASE IN RABBITS Masaki Yoshida, Koichi Masunaga, Takashi Nagata, Akito Inadome, Yutaka Miyamoto, Tomomi Haba, and Junzo Kudoh Masaki YoshidaMasaki Yoshida Kumamoto, Japan More articles by this author , Koichi MasunagaKoichi Masunaga Tokyo, Japan More articles by this author , Takashi NagataTakashi Nagata Saitama, Japan More articles by this author , Akito InadomeAkito Inadome Kumamoto, Japan More articles by this author , Yutaka MiyamotoYutaka Miyamoto Kumamoto, Japan More articles by this author , Tomomi HabaTomomi Haba Kumamoto, Japan More articles by this author , and Junzo KudohJunzo Kudoh Kumamoto, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.609AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recently, we demonstrated that chronic hyperlipidemia caused bladder dysfunction including detrusor overactivity in heritable hyperlipidemic rabbits (WHHLMI rabbits). Various pathologic conditions cause prostaglandins synthesis in both bladder smooth muscle and mucosa, resulting in bladder dysfunction. To evaluate the effects of hyperlipidemia on lower urinary tract function, we examined the relationship between hyperlipidemia-induced bladder dysfunction and urinary prostaglandin E2 (PGE2) level in WHHLMI rabbits. METHODS WHHLMI rabbits and the age and sex-matched Japanese white rabbits (control group) were prepared. In all rabbits, the urinary volume and frequency were recorded for three days, and 24-h urine samples of all rabbits were collected. Cystometrograms were performed under anesthesia using constant infusion of saline into the bladder to elicit voiding, and voided volume, residual urine, micturition pressure, and micturition interval were evaluated. 24-h urinary PGE2 levels were assayed by enzyme immunoassay (EIA) by using PGE2 EIA kit-Monoclonal. In addition, immunohistochemical staining of COX-2 of bladder tissue of WHHLMI and control rabbits was performed, using mouse monoclonal anti-COX-2 antibody. RESULTS The number of micturition per day was higher in WHHLMI rabbits (4.24±1.07 times/day) than in control rabbits (1.8±0.3 times/day), and the voided volume was lower in WHHLMI rabbits (14.81±4.60 ml) than in control rabbits (43.8±5.1 ml). In cystometrograms, WHHLMI rabbits showed detrusor overactivity, higher frequency of micturition (7.55±1.25 times/20 min) and lower voided volume (6.92±1.5 ml) than in control rabbits (1.44 ± 2.51 times/20 min and 20.8±3.2 ml, respectively). The urinary excretion of PGE2 was significantly higher in WHHLMI rabbits (6.44±1.87 ng/ml) than in control rabbits (0.91±0.14 ng/ml). Analysis of relationship between parameters of bladder function and urinary PGE2 level in WHHLMI rabbits indicated a significantly negative correlation (r=0.81) between urinary PGE2 level and voided volume, and a significant positive correlation between urinary PGE2 level and the number of micturition (r=0.86). Immunohistochemical staining of COX-2 showed a significant higher immunoreactivity in bladder mucosa of WHHLMI rabbits, as compared to control. CONCLUSIONS The present study suggested that chronic hyperlipidemia caused increase of COX-2 activity in bladder mucosa, which might cause the enhanced PGE2 release, resulting in activation of sensory input and detrusor overactivity. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e318 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masaki Yoshida Kumamoto, Japan More articles by this author Koichi Masunaga Tokyo, Japan More articles by this author Takashi Nagata Saitama, Japan More articles by this author Akito Inadome Kumamoto, Japan More articles by this author Yutaka Miyamoto Kumamoto, Japan More articles by this author Tomomi Haba Kumamoto, Japan More articles by this author Junzo Kudoh Kumamoto, Japan More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Urinary nerve growth factor but not prostaglandin E2 increases in patients with interstitial cystitis/bladder pain syndrome and detrusor overactivity

To compare urinary nerve growth factor (NGF) and prostaglandin E2 (PGE2) levels among patients with detrusor overactivity (DO), increased bladder sensation (ISB), interstitial cystitis/bladder pain syndrome(IC/BPS) and controls. Urine samples were collected from 40 women with IC/BPS, 54 with overactive bladder (OAB) and 27 normal women as controls, all with a full bladder. Patients with OAB were further classified into subgroups of DO or IBS by urodynamic results. Urinary NGF and PGE2 levels were measured using an enzyme-linked immunosorbent assay. Urinary NGF and PGE2 levels were normalized by urinary creatinine (Cr) levels and compared among all subgroups. Urinary NGF levels were increased in the 40 women with IC/BPS and 23 with DO but not in 31 with IBS and the 27 controls. Mean (sd) urinary NGF/Cr levels were not significantly different between patients with IC/BPS, at 1.35 (0.36), and DO, at 1.93 (0.77). Urinary NGF/Cr levels were significantly higher in women with IC/BPS than in women with IBS, at 0.25 (0.10) (P=0.01). Using receiver operating characteristic curves for assessing urinary NGF/Cr levels in patients with IC/BPS and IBS, IC/BPS was diagnosed with a sensitivity and specificity of 75% and 65.5%, respectively, based on a urinary NGF/Cr threshold of 0.015. However, urinary PGE2/Cr levels were not significantly different among all subgroups. Urinary NGF/Cr levels are elevated in women with IC/BPS or DO, but not in those with IBS. The differential diagnosis of women with IC/BPS from those with frequency-urgency syndrome is possible based on urinary NGF/Cr levels but not urinary PGE2/Cr level.