6-ketoprostaglandin-f1-alpha and Albuminuria

We have previously shown nutritional intervention with fish oil (n-3 PUFA) to reduce numerous complications associated with the metabolic syndrome (MetS) in the JCR:LA-corpulent (cp) rat. In the present study, we sought to explore the potential role of fish oil to prevent glomerulosclerosis in JCR:LA-cp rats via renal eicosanoid metabolism and lipidomic analysis. Male lean and MetS JCR:LA-cp rats were fed a lipid-balanced diet supplemented with fish oil (5 or 10 % of total fat). After 16 weeks of feeding, albuminuria was significantly reduced in MetS rats supplemented with 5 or 10 % fish oil ( - 53 and - 70 %, respectively, compared with the untreated MetS rats). The 5 % fish oil diet resulted in markedly lower glomerulosclerosis ( - 43 %) in MetS rats and to a lesser extent in those supplemented with 10 % fish oil. Interestingly, untreated MetS rats had higher levels of 11- and 12-hydroxyeicosatetraenoic acids (HETE) v. lean rats. Dietary fish oil reduced these levels, as well as other (5-, 9- and 15-) HETE. Whilst genotype did not alter prostanoid levels, fish oil reduced endogenous renal levels of 6-keto PGF1α (PGI2 metabolite), thromboxane B2 (TxB2), PGF2α and PGD2 by approximately 60 % in rats fed 10 % fish oil, and TxB2 ( - 50 %) and PGF2α ( - 41 %) in rats fed 5 % fish oil. In conclusion, dietary fish oil prevented glomerular damage in MetS rats and mitigated the elevation in renal HETE levels. These results suggest a potential role for dietary fish oil to improve dysfunctional renal eicosanoid metabolism associated with kidney damage during conditions of the MetS.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Dietary Fats; Dietary Supplements; Dinoprost; Disease Models, Animal; Fish Oils; Genotype; Hydroxyeicosatetraenoic Acids; Kidney Diseases; Kidney Glomerulus; Male; Metabolic Syndrome; Prostaglandin D2; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

Therapies that target the vascular endothelial growth factor (VEGF) pathway cause hypertension, but the mechanism remains unknown. This cross-sectional study tested the hypothesis that VEGF inhibition causes hypertension by suppressing VEGF-mediated vasodilatory pathways. Urine was collected from 80 patients with metastatic renal cell carcinoma from 2002 to 2009, 40 at baseline and 40 while on VEGF inhibitors. Measured urinary biomarkers include albumin, metabolites of the nitric oxide (NO) pathway and its downstream effector cGMP, and prostaglandin pathway biomarkers prostaglandin E2, 6-keto prostaglandin F1α, and cAMP, all normalized to urinary creatinine. The mean age in both groups was 61.8 years, 76% were men, and urinary albumin was higher in patients receiving VEGF inhibitors (median: 18.4 versus 4.6 mg/g; P = 0.009). cGMP/creatinine was suppressed in patients on VEGF inhibitors (0.28 versus 0.39 pmol/μg; P = 0.01), with a trend toward suppression of nitrate/creatinine (0.46 versus 0.62 μmol/mg; P = 0.09). Both comparisons were strengthened when patients on bevacizumab were excluded, and only those receiving small molecule tyrosine kinase inhibitors were analyzed (cGMP/creatinine: P = 0.003; nitrate/creatinine: P = 0.01). Prostaglandin E2, 6-keto prostaglandin F1α, and cAMP did not differ between groups. These results suggest that hypertension induced by VEGF inhibitors is mediated by suppression of NO production. Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF-targeted therapies.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Cross-Sectional Studies; Cyclic AMP; Cyclic GMP; Dinoprostone; Enzyme Inhibitors; Female; Humans; Hypertension; Kidney Neoplasms; Male; Middle Aged; Nitric Oxide; Protein-Tyrosine Kinases; Vascular Endothelial Growth Factor A

To study the modifying effect and mechanism of Tangshenning Recipe on micro-albuminuria in rats with early diabetic nephropathy (DN).. Male Wistar rats were randomly divided into the normal group (n=8) and model group (n=24). Intraperitoneal injecting of streptozotocin (STZ) plus complete Freund's adjuvant (CFA) was applied once a week for 3 times to induce the DN rats model. Three weeks later, the model group rats were randomly divided into pathologic group (n=8), monopril group (n=8) and Tangshenning Recipe group(n=8) according to the 24 h U-Alb. Each group's renal hemodynamics index and SOD, GSH, MDA in renal tissue were determined by radioimmunoassay (RIA) and colorimetric method respectively.. The levels of plasmatic TXB(2), the ratio of TXB(2) and 6-keto-PGF1alpha, and the CGRP in pathologic group were significantly higher than those in normal group. The levels of plasmatic ET decreased obviously, SOD decreased and MDA increased significantly in the rats' renal tissue of pathologic group. The levels of plasmatic TXB(2), the ratio of TXB(2) and 6-keto-PGF1alpha decreased significantly in both Tangshenning Recipe group and monopril group, and the therapeutic effect of Tangshenning Recipe group was better than that of monopril group. SOD was higher and MDA was lower in Tangshenning Recipe group than that in pathologic group.. The results indicates that Tangshenning Recipe can lower the micro-albuminuria in early DN rats, the mechanism of which probably lies in the modification of glycometabolism, the ratio of TXB(2) and 6-keto-PGF1alpha, the plasmatic CGRP and the renal lipid preoxidation.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Diabetic Nephropathies; Disease Models, Animal; Drugs, Chinese Herbal; Glutathione; Male; Malondialdehyde; Phytotherapy; Radioimmunoassay; Random Allocation; Rats; Rats, Wistar; Superoxide Dismutase; Thromboxane B2; Treatment Outcome

1. The obese fa/fa Zucker rat is a genetic model of obesity and insulin resistance which develops a number of metabolic and endocrine features of non-insulin-dependent diabetes, including hypertension, proteinuria and glomerular sclerosis. 2. We have investigated the urinary excretion of the metabolites of thromboxane (thromboxane B2) and prostacyclin (6-keto prostaglandin F1 alpha), and of endothelin and cyclic GMP as markers for changes in the balance of renal haemodynamic factors in the obese Zucker rat. 3. Obese fa/fa Zucker rats were hypertensive compared with their lean counterparts (161 +/- 3 and 138 +/- 3 mmHg respectively, P < 0.01); obese animals were also markedly proteinuric (16.7 +/- 6.7 versus 1.1 +/- 0.1 mg/ml) and albuminuric (8.3 +/- 2.9 versus 0.4 +/- 0.25 mg/ml) and excreted less creatinine than lean animals (all P < 0.01). Urinary excretion of endothelin was greater in obese rats (123 +/- 24 versus 62 +/- 10 pg/15 h, P < 0.05) as was the level of pre-proendothelin mRNA, but excretion of cyclic GMP was depressed (12.5 +/- 1.6 versus 27.2 +/- 3.1 nmol/ 15 h, P < 0.01). Histological examination of kidneys from obese animals showed evidence of focal glomerulosclerosis and cortical tubular damage. 4. These results show that increased urinary endothelin is associated with proteinuria and early stage nephropathy in this animal model of non-insulin-dependent diabetes mellitus. This finding, coupled with a decreased excretion of cyclic GMP, suggests that these increased renal vasoconstrictor/vasodilator forces might contribute to the renal functional changes in non-insulin-dependent diabetes mellitus.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Cyclic GMP; Diabetes Mellitus; Diabetes Mellitus, Type 2; Endothelin-1; Immunohistochemistry; Kidney; Male; Obesity; Rats; Rats, Zucker; RNA, Messenger; Statistics, Nonparametric; Thromboxane B2

In this study, we investigated the effect of captopril (CPT) on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), filtration fraction (FF), urinary albumin excretion (UAE) and daily urinary excretion of thromboxane B2 (TXB2) and 6-keto- prostaglandin F1a (6-keto-PGF1a) in 29 normotensive non-insulin-dependent diabetes (NIDDM) patients without clinically discernible nephropathy. Before treatment, urinary excretion 6-keto-PGF1a was significantly increased (P < 0.05) in 29 NIDDM patients compared with 25 health subjects matched for age and sex. The values of GFR and FF were significantly higher (P < 0.01 and P < 0.005, respectively) in NIDDM than in normal volunters, whereas ERPF was comparable in both groups. Meanwhile we observed that UAE of early NIDDM was increased before treatment. After CPT treatment, GFR, FF, UAE and urinary excretion of 6-keto-PGF1a were significantly reduce (all P < 0.005) compared with those of NIDDM before treatment. These data indicated that CPT is effective in lowering glomerular filtration pressure and ameliorating microalbuminuria in the normotensive early NIDDM.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Male; Matched-Pair Analysis; Middle Aged; Prostaglandins; Renal Plasma Flow; Thromboxane B2

Wistar rats (4-week-old) were administered with streptozotocin (45 mg/kg) through tail veins. After 3 months, diabetic rats were divided into 2 groups. One group (EPA group, n = 16) was fed a lipid-free diet (90%, w/w) plus lard (8%) and 90% pure eicosapentaenoic acid ethyl ester (2%) for 6 months. The other group (control group, n = 16) was fed in the same way except that eicosapentaenoic acid ethyl ester was replaced by safflower oil. Twenty-four-hour urine was collected just before starting the experimental diets and during the 6-month experimental period at monthly intervals. There were no differences in food intake and body weight between the two groups throughout the experiment. The mean microalbuminuria of the EPA group became significantly lower than that of the control group after 4 months on the diets through the end of the study (6 months). The mean microalbuminuria levels at the end of the study were 1.38 mg/day in the EPA group (n = 9) and 5.19 mg/day in the control group (n = 6) (p < 0.01). Eicosapentaenoic acid administration might retard the progression of diabetic nephropathy by reducing microalbuminuria.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Eating; Eicosapentaenoic Acid; Fatty Acids; Kidney; Lipids; Male; Organ Size; Rats; Rats, Wistar; Thromboxane B2; Weight Gain

In order to assess the effects of long-term exposure to cadmium (Cd) on the renal metabolism of eicosanoids, the urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), and thromboxane B2 (TXB2) was determined in 37 workers exposed to Cd and in female Sprague-Dawley rats given 100 ppm Cd in drinking water for 10 months. Urinary output of sodium and calcium was also determined. The Cd-exposed workers showed an increased urinary concentration of 6-keto-PGF1 alpha, PGE2, sodium, and calcium. The rise of 6-keto-PGF1 alpha was related to Cd levels in blood and weakly correlated with urinary sodium. Calcium in urine was not related to the concentration of the metal in blood and urine. A slight elevation in urinary TXB2 was also observed in workers with blood Cd higher than 5 micrograms/liter. After 10 months of exposure to Cd, female Sprague-Dawley rats presented an enhanced urinary excretion of albumin, transferrin, beta 2-microglobulin, sodium, and PGE2 in urine. The latter was significantly correlated with albuminuria and transferrinuria. In conclusion the results show that chronic exposure to Cd induces changes in the urinary excretion of some eicosanoids. The possible relation of these changes to Cd-induced kidney dysfunction are discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylglucosaminidase; Albuminuria; Animals; beta 2-Microglobulin; Cadmium; Calcium; Dinoprostone; Eicosanoids; Female; Humans; Kidney; Kidney Glomerulus; Male; Occupational Exposure; Proteinuria; Rats; Rats, Sprague-Dawley; Sodium; Time Factors; Transferrin

The effect of two structurally unrelated aldose reductase inhibitors, sorbinil and ponalrestat, on glomerular prostaglandin production and urinary albumin excretion was investigated in rats with diabetes induced by streptozotocin. It was found that both aldose reductase inhibitors, when administered from the time of induction of the diabetes, significantly decreased the raised urinary albumin excretion in the diabetic rats, although it remained elevated compared with non-diabetic rats. Glomerular prostaglandin E and 6-keto-prostaglandin F1 alpha production was significantly increased in glomeruli obtained from the diabetic rats. Inhibition of aldose reductase caused a reduction in the raised glomerular prostaglandin production, although this remained above that observed in the non-diabetic rats. Subsequent experiments were performed to determine whether the effects of the aldose reductase inhibitors could be explained by effects on glomerular filtration rate. It was found that ponalrestat, at a dose which markedly reduced urinary albumin excretion, did not significantly affect glomerular filtration rate in non-diabetic rats, rats with untreated streptozotocin-induced diabetes and rats with diabetes partially treated with low dose insulin. Glomerular sorbitol concentrations were significantly elevated in untreated diabetic rats as early as two weeks after the induction of diabetes. It is concluded that the administration of aldose reductase inhibitors from the time of induction of diabetes significantly reduces glomerular prostaglandin production and urinary albumin excretion. The latter effect is not due to an effect on glomerular filtration rate. Increased polyol pathway activity may account in part for the increased glomerular prostaglandin production and urinary albumin excretion in early experimental diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Glomerular Filtration Rate; Hypoglycemic Agents; Imidazoles; Imidazolidines; Kidney Glomerulus; Male; Phthalazines; Prostaglandins E; Rats; Rats, Inbred Strains; Reference Values

Recently the beneficial effects of captopril (angiotensin-converting-enzyme inhibitor) on diabetic nephropathy, especially proteinuria, have been reported by some investigators. The mechanism whereby proteinuria is reduced, however, have not been clarified yet. The present study was undertaken to evaluate the effects of captopril on urinary albumin excretion in relation to urinary prostaglandins (PGs) excretion in patients with non-insulin-dependent diabetes mellitus (NIDDM). Captopril (37.5 mg/day) was orally administered to 13 diabetic patients for an eight-week period. A single administration of captopril (12.5 mg) was performed in the same patients. The spot urine samples were collected in the early morning and 2 hr after the single administration of captopril. The albumin index (mg/gram-creatinine) was markedly decreased in eight patients (Group A) within four weeks, but no decrease was found in five patients (Group B). Furthermore, in Group A, by the single administration of captopril urinary excretions of 6-keto-PCF1 alpha (a stable metabolite of PGI2) and PGE2 were significantly (p less than 0.05) increased while urinary TXB2 (a stable metabolite of TXA2) excretion did not change significantly. The urinary 6-keto-PGF1 alpha/TXB2 ratio, which is significantly (p less than 0.05) low in diabetic patients was significantly (p less than 0.01) increased up to the normal value in Group A. In Group B, however, there were no significant changes in urinary PGs excretion. These results suggest that captopril enhances the production of intrarenal vasodilatory PGs such as PGI2 and PGE2, which may be deeply involved in the reduction of intraglomerular capillary pressure and urinary protein excretion in diabetic patients.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Prostaglandins; Thromboxane B2

Triflusal (2-acetoxy-4-trifluormethylbenzoic acid) is a platelet-antiaggregant drug that selectively inhibits thromboxane synthesis with little effect on prostacyclin production. In this study, we evaluated the effect of 5-day administration of 900 mg/day triflusal on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary albumin excretion (UAE), thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (PGF1 alpha), and PGE2 in nine normotensive insulin-dependent diabetic patients with UAE between 30 and 103 micrograms/min. Plasma TXB2 and plasma renin activity (PRA) were also determined. After administration of triflusal, we observed a reduction in microalbuminuria (59 +/- 25 vs. 33 +/- 22 micrograms/min, P less than 0.01), an increase in RPF (648 +/- 119 vs. 722 +/- 134 ml.min-1 x 1.73 m-2, P less than 0.01), and a reduction in filtration fraction (0.24 +/- 0.04 vs. 0.20 +/- 0.03, P less than 0.01). Triflusal produced a significant reduction in both plasma TXB2 (130 +/- 39 vs. 52 +/- 32 pg/ml, P less than 0.02) and urine TXB2 (523 +/- 249 vs. 312 +/- 11 pg/min, P less than 0.02), without changes in PRA and UAE of 6-keto-PGF1 alpha and PGE2. Metabolic control and arterial blood pressure did not change during the study. These results suggest that platelet-antiaggregant therapy can reduce microalbuminuria in diabetic patients. This effect could be mediated by a reduction in the transglomerular hydraulic pressure through a vasodilation of efferent arterioles secondary to renal thromboxane synthesis inhibition.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 1; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Male; Platelet Aggregation Inhibitors; Renal Circulation; Renin; Salicylates; Thromboxane B2

The efficacy of dietary intervention with either 6% protein restriction, fish oil or safflower oil was assessed in the remnant nephron model. Female Munich Wistar rats were prefed for one week prior to 5/6 nephrectomy and followed for the ensuing 28 days. Fish oil, safflower oil and protein restriction prevented the gammaglobulinuria but only fish oil lessened the albuminuria in this model. The remnant nephrons of the fish oil treated rats contained less arachidonic acid and greater quantities of eicosapentaenoic and docosahexaenoic acid than the safflower oil or lab chow fed control rats. The fish oil, and to a lesser extent the safflower oil, treated animals had a higher ratio of 6 keto PGF1 alpha to TX B2 metabolites in their urine. We suggest these changes may be responsible for the lessening in urine protein excretion. Fish oil feeding was more effective than severe protein restriction or safflower oil dietary supplementation in lessening both the gammaglobulinuria and albuminuria of the remnant nephron model.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Arachidonic Acids; Dietary Fats; Dietary Proteins; Fatty Acids, Unsaturated; Female; Fish Oils; Immunoglobulin G; Nephrectomy; Nephrons; Proteinuria; Rats; Safflower Oil; Thromboxane B2

The acute effect of inhibition of prostaglandin synthesis with indomethacin 50 mg by mouth on renal haemodynamics has been examined in 8 male Type 1 diabetic patients with elevated glomerular filtration rate who were free of diabetic complications. Renal plasma flow and glomerular filtration rate were measured by constant infusion of para-amino hippurate and polyfructosan, the patients being studied at normoglycaemia. Urinary excretion of prostaglandin E2 fell from 885 +/- 160 to 345 +/- 115 pg min-1, and excretion of 6-keto-prostaglandin F1 alpha fell from 489 +/- 77 to 283 +/- 50 pg min-1. There was no change in renal plasma flow or glomerular filtration rate following indomethacin. The results do not support the hypothesis that increased renal prostaglandin synthesis is a cause of hyperfiltration in diabetes mellitus.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Albuminuria; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Dinoprostone; Glomerular Filtration Rate; Humans; Indomethacin; Kidney; Male; Prostaglandins; Renal Circulation; Sodium