6-ketoprostaglandin-f1-alpha and Proteinuria

The effects of dietary protein on glomerular and hormonal function were studied in twelve adults with a variety of glomerular diseases. They were randomly assigned, using a crossover design, to two 11-day periods, one on a high-protein diet (2 g.kg-1.day-1) and the other on a low-protein diet (0.55 g.kg-1.day-1). Improvement in glomerular permselectivity on the low-protein diet was manifested by a decreased 24-h urinary excretion of total protein, albumin, and IgG by 33, 40, and 25%, respectively (all P less than 0.02); a fall in the fractional clearance of albumin (10.1 +/- 6.3 X 10(-3) to 5.8 +/- 3.3 X 10(-3)), and IgG (6.9 +/- 5.1 X 10(-3) to 3.5 +/- 2.3 X 10(-3)) (both P less than 0.02); and a decreased fractional clearance of neutral dextrans of molecular radii 48-56 A (P less than 0.05), when measured on the final day of each dietary period. The high-protein diet was accompanied by a higher plasma renin activity (6.9 +/- 1.6 vs. 3.5 +/- 0.8 ng angiotensin I.ml-1.h-1) (P less than 0.02), and increased excretion of prostaglandin E and 6-ketoprostaglandin F1 alpha. We conclude that a low-protein diet rapidly improves the size-selective defect in glomerular permselectivity.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aldosterone; Blood Proteins; Dextrans; Diabetic Nephropathies; Dietary Proteins; Female; Glomerulonephritis; Hemodynamics; Hormones; Humans; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Male; Metabolic Clearance Rate; Middle Aged; Prostaglandins E; Proteinuria; Renin

To study the effects of high-protein diet (HPD) and high-grade proteinuria in aggravating the progression of chronic renal failure (CRF) in rats.. CRF with high-grade proteinuria was induced by supplying HPD in five sixth nephrectomy rats, and the changes of serum creatinine (Scr), blood urea nitrogen (BUN), endothelin-1 (ET-1), thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F(l alpha) (6-Keto-PGF(l alpha)) were observed. At the same time, the content of malondialdehyde (MDA), and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase(SOD)were measured in blood and renal tissue of the rats.. HPD and high-grade proteinuria could accelerate the damage of kidney through increasing the levels of ET-1 and TXB(2), reducing the level of 6-Keto-PGF(l alpha), and attenuating the activities of SOD and GSH-Px.. HPD can accelerate the damage of kidney through inducing the high-grade proteinuria in five sixth nephrectomy rats, influencing the expression of kidney vasoactive substance, and reducing the anti-oxidation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatinine; Dietary Proteins; Disease Progression; Endothelin-1; Glutathione Peroxidase; Kidney Failure, Chronic; Liver; Male; Malondialdehyde; Nephrectomy; Proteinuria; Random Allocation; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

To explore the effects of ligustrazine on proteinuria, urinary TxB2 (metabolism of thromboxane A2, TxA2) and 6-keto-PGF1alpha (metabolism of prostacyclines I2, PG I2), glomerular inducible nitric oxide(NO) synthase (iNOS) mRNA, urinary NO3-/NO2- (decomposing products of NO) and pathological changes in rats with passive Heymann nephritis (PHN).. A rat PHN model was induced by intravenous injection of rabbit anti-rat renal tubular antigen (Tub-Ag) antiserum, and ligustrazine was given intraperitoneally into PHN rats every 2 days for 1-5 weeks. Then, proteinuria, urinary TxB2 and 6-keto-PGF1alpha, glomerular iNOS mRNA, and urinary NO3-/NO2- were measured by sulfosalicylic acid, radioimmunoassay (RIA), Northern blot and nitric acid reductase methods, respectively. Moreover, the damage to the renal tissue of the rats was observed under light and electron microscopy and immunofluorescence (IF).. The urinary TxB2 in PHN rats was significantly higher than that in control rats, but the PHN rats treated with ligustrazine had significantly less proteinuria, urinary TxB2 and tissue lesions, and more urinary 6-keto-PGF(1alpha), glomerular iNOS mRNA and urinary NO2-/NO3- than the PHN rats without the administration of ligustrazine.. These data indicate that ligustrazine has inhibitory roles on the glomerular injury of PHN rats, which may associate with modulating the balance of TxA2-PGI2 and elevating synthesis of NO to a certain extent.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Female; Fluorescent Antibody Technique, Direct; Glomerular Basement Membrane; Glomerulonephritis; Immunoglobulin G; Kidney Glomerulus; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Proteinuria; Pyrazines; Rats; RNA, Messenger; Thromboxane A2

We used rats (the Otsuka Long-Evans Tokushima Fatty strain) as a model of type 2 diabetes to find whether thromboxane (TX) A2 is involved in diabetic nephropathy, and if so, to identify where it is synthesized. We measured urinary excretion of TXB2 and 2,3-dinor-TXB2 in rats up to 60 weeks of age as markers of renal and platelet synthesis of TXA2, respectively. Some diabetic rats were given daily oral doses of OKY-046 (100 mg/kg), a TXA2 synthase inhibitor, starting when they were 10 weeks of age. Healthy Long-Evans Tokushima Otsuka rats served as the controls. Urinary excretion of protein was greater in diabetic rats at 26 weeks than in controls, and the difference increased with age. Urinary excretion of TXB2 by diabetic rats was about 150% that of controls at 14 weeks, and remained at that level. In diabetic rats, urinary excretion of 2,3-dinor-TXB2 increased with age in parallel to increases in proteinuria, but in controls, excretion of these metabolites did not change with age. In diabetic rats, OKY-046 prevented the increase in urinary excretion of both metabolites, and decreased the proteinuria. Histologic examination at 60 weeks showed intraglomerular thrombi in diabetic rats but not in controls. OKY-046 reduced intraglomerular thrombi formation and the score for glomerulosclerosis. When platelet aggregation began, more TXA2 than before was released from the thrombi that formed, and the TXA2 contributed to the progress of nephropathy in this rat model of type 2 diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enzyme Inhibitors; Glomerular Mesangium; Male; Methacrylates; Prostaglandins; Proteinuria; Rats; Rats, Inbred OLETF; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

In this study we investigated the role of a mixture of n-6/n-3 essential fatty acids, in the cyclosporine model nephrotoxicity. Administration of cyclosporine in rats decreased creatinine clearance and provoked body weight loss, but it did not induce proteinuria and did not alter the urine volume. These changes were associated with decreased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that 100% of the animals were affected by histological tubular lesions on their kidneys. Administration of cyclosporine to animals fed for 3 months on standard chow containing a mixture of n - 6/n - 3 essential fatty acids, restored creatinine clearance, augmented urine volume and prevented body weight loss. The improvement of renal function was accompanied by increased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that only 40% of the animals demonstrated histological tubular lesions, of minor importance, to their kidneys. Our results suggest that the metabolites of arachidonic acid can play important role in the development of cyclosporine-nephrotoxicity because they increase the levels of thromboxane A and that the enchanced synthesis of prostaglandins (E) and (I) induced by a mixture of n - 6/n - 3 essential fatty acids, could play a beneficial role in the prevention of this renal dysfunction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclosporine; Dietary Fats, Unsaturated; Dinoprostone; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Kidney; Kidney Diseases; Prostaglandins I; Proteinuria; Rats; Rats, Wistar; Thromboxane B2; Weight Loss

Approaches to the treatment of lupus nephritis include immunosuppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. Mycophenolate mofetil (MMF) has been described as being less toxic than conventional immunosuppressants, and it was effective in preventing progressive nephritis in lupus mice. Our study evaluated the therapeutic effect of MMF in NZB/W F1 hybrid mice with established disease. We also examined the combination of MMF with a selective cyclooxygenase-2 (COX-2) inhibitor, DFU, based on previous findings of excessive renal production of COX-2-derived thromboxane A2 (TXA2) in lupus nephritis.. Four groups of NZB/W mice (N = 30 each group), starting at five months of age, were given daily by gavage the following: vehicle, MMF 60 mg/kg, DFU 3 mg/kg, or MMF + DFU. Fifteen mice for each group were used for the survival studies, and the remaining mice were sacrificed at nine months.. MMF or DFU alone partially delayed the onset of proteinuria compared with vehicle. Combined therapy was significantly (P < 0.05) more effective than single drugs. Animal survival was partially ameliorated by MMF and significantly improved by the drug combination in comparison with the vehicle (P = 0.005) and DFU alone (P < 0.03). At nine months, serum blood urea nitrogen (BUN) levels were lower in all of the treated groups than in the vehicle group. Renal damage was also limited, but to a greater extent in mice given the combined therapy. In untreated mice, renal COX-2 mRNA expression was up-regulated, and generation of TXB(2), the stable breakdown product of TXA(2), increased. DFU prevented the abnormal renal TXB(2) production, confirming the COX-2 origin of this eicosanoid, whereas renal 6-keto-PGF(1 alpha) and prostaglandin E(2) (PGE(2)) were not affected substantially.. These results offer a strong case for exploring the possibility that in humans MMF combined with COX-2 inhibitors has a role in the treatment options for lupus nephritis. This combined drug therapy may be at least as effective as steroids but without the obvious nephrotoxicity of the latter.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies, Antinuclear; Blood Urea Nitrogen; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Female; Furans; Gene Expression Regulation, Enzymologic; Immunosuppressive Agents; Isoenzymes; Kidney; Lupus Nephritis; Lymphocyte Count; Lymphocyte Subsets; Membrane Proteins; Mice; Mice, Inbred NZB; Mycophenolic Acid; Prostaglandin-Endoperoxide Synthases; Proteinuria; Spleen; Survival Rate; Thromboxane B2

No data are available about the effects of AT1 receptor antagonist losartan on the skeleton and there is also little information on the activity of an ACE inhibitor enalapril on bone metabolism. It is widely believed that the vasculature plays an important role in bone remodeling under normal and pathological conditions. We treated 14-week-old female Wistar rats with losartan, enalapril or saline. Administration of the ACE inhibitor enalapril and angiotensin II antagonist losartan had no effect on total malondialdehyde (MDA) in the blood and on urinary excretion of some eicosanoids and their metabolites. The administration of enalapril and losartan in a dose recommended for the treatment of hypertension did not cause significant changes in bone density, the ash and mineral content or morphometric parameters of the femur compared to the values found in control female rats.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Bone Density; Dinoprost; Dinoprostone; Enalapril; F2-Isoprostanes; Female; Femur; Losartan; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Thromboxane B2

1. Several lines of evidence indicate that thromboxane (Tx) A2 may contribute to the development and maintenance of hypertension. The present study was undertaken to evaluate the role of TxA2 in the development of hypertension in spontaneously hypertensive rats (SHR) by using an orally active, highly specific TxA2/prostaglandin H2 receptor antagonist S-1452. 2. Vehicle (1% arabic gum solution) alone was given orally to Wistar-Kyoto (WKY) rats (n = 15) and SHR (n = 14), while S-1452 (10 mg/kg per day, twice daily) was administered orally to SHR (n = 16) for 18 weeks (from 5 to 23 weeks of age). 3. No significant difference was observed in tail-cuff blood pressure (BP) between vehicle- and S-1452-treated SHR before and at 5 and 11 weeks after treatment. Thereafter, BP was further elevated in vehicle-treated SHR, but was significantly blunted in SHR treated with S-1452 at 15 (224+/-8 vs 211+/-13 mmHg; P < 0.01) and 18 weeks (227+/-9 vs 206+/-10 mmHg; P < 0.001); this was associated with reduced proteinuria. 4. Urinary TxB2 in vehicle-treated SHR, especially during the early period, was significantly greater than that in WKY rats, while no significant difference was observed in urinary 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) between the two groups. Treatment with S-1452 reduced urinary excretion of TxB2 at 18 weeks. 5. The present study shows that S-1452, at the dose used, does not reduce BP during the early period of the development of hypertension. These results suggest that the role of enhanced TxA2 production in the development of hypertension is small, if any, in SHR. Delayed response of BP may be independent of the direct pharmacological effects of S-1452.

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Animals; Antihypertensive Agents; Blood Pressure; Bridged Bicyclo Compounds; Dinoprostone; Fatty Acids, Monounsaturated; Hypertension; Male; Potassium; Prostaglandin Antagonists; Prostaglandins; Prostaglandins H; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Prostaglandin; Receptors, Thromboxane; Renin; Sodium; Thromboxane B2; Time Factors

Cyclosporine (CsA) (45 mg/kg/day for 7 days) administration in female Wistar rats induced significant decrease in creatinine clearance (Ccr) and body weight loss (BWL). Urine volume (V) was not altered and proteinuria (PU) not provoked. These changes were associated with increased urinary endothelin 1 (ET-1) and thromboxane B(2)(TXB(2)) concentrations, and decreased urinary ratios of prostaglandin (6ketoPGF(1 alpha)and PGE(2)) to TXB(2)excretions. Nifedipine (NFD) (0.1 mg/kg/day for 7 days), a calcium channel blocker, administrated in addition to CsA, to another group of animals, significantly augmented Ccr and urine V but did not prevent BWL in comparison to CsA-only treated rats. The urinary ET-1 and TXB(2)concentrations displayed significant and non-significant decrease respectively, while the urinary excretion ratios of 6ketoPGF(1 alpha)/TXB(2)and PGE(2)/TXB(2)were significantly enhanced.These observations indicate that the partial protection of NFD in CsA-induced nephrotoxicity could be attributed to augmented urinary prostanoid ratios of renal vasodilators (6ketoPGF(1 alpha)and PGE(2)) to vasoconstrictor (TXB(2)) excretions, and also to reduced release of rather renal origin ET-1, the most potent mamalian vasoconstrictor peptide known to date. In a previous study, we found that NFD only slightly prevented structural renal damage, induced by CsA. So, the NFD protection refers only to functional toxicity and not to structural damage, mediated at least in part by the preservation of relatively high renal TXB(2)levels. However, other nephrotoxic factors and additional mechanisms could also be implicated in this CsA-induced syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Calcium Channel Blockers; Creatinine; Cyclosporine; Dinoprostone; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Enzyme Inhibitors; Female; Immunoassay; Kidney; Nifedipine; Proteinuria; Rats; Rats, Wistar; Spectrophotometry; Thromboxane B2; Urine

To clucidate the mechanism of the therapeutic effect of Yiqi Huoxue (YQHX) serial recipes on membranous nephritis.. Forty-nine New Zealand male rabbits were made to menbranous nephritis model by cation bovine serum albumin and divided into 5 groups, the group A (treated by Qingre Moshen granule), B (treated by Bushen Moshen granule), C (treated by steroid), D (the control group) and E (the normal group). Twenty-four hours' urinary protein content of the animals was determined every week, and plasma albumin, blood lipid, renal function and prostaglandins were tested by the end of experiment. And pathological changes of basement membrane were observed by using light, electronic and immunofluorescent microscopy with polyethylene imine stain.. The 24 hours urinary protein content, plasma albumin and blood lipid in the group A and B were lower than those in the control group significantly, P < 0.01 or 0.05, while those in the group C and the D were similar, P > 0.05. In comparing the group A and B with the group C, the difference was also significant, P < 0.05. Light, electronic and immunofluorescent microscopic examination all showed that the pathologic changes in the group A, B and C were lesser than that of the control, the effect was in the order A > B > C.. YQHX serial recipes can reduce urinary protein content, elevate plasma albumin level, restore the charge barrier effect of and attenuate the immune complex deposition on the basement membrane of glomeruli.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Basement Membrane; Drugs, Chinese Herbal; Glomerulonephritis, Membranous; Male; Proteinuria; Rabbits; Random Allocation; Serum Albumin; Thromboxane B2

The antinephritic effect of lipo-prostaglandin E1, prostaglandin E1 ((1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopent ane heptanoic acid) incorporated in lipid microspheres was investigated using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane nephritis. Lipo-prostaglandin E1 was given i.v. twice a day at 20, 40 and 80 microg/kg and azathioprine, an immunosuppressive agent, at 20 mg/kg was given p.o. once daily from the autologous phase, in which glomerulonephritis was fully developed (the 21 st day after injection of the anti-glomerular basement membrane serum), to the 50th day. Lipo-prostaglandin E1 (40 and 80 microg/kg x 2 per day) significantly inhibited the development of glomerular alterations as well as the elevation of proteinuria and plasma creatinine. Lipo-prostaglandin E1 (20 microg/kg x 2 per day) and azathioprine (20 mg/kg per day) significantly inhibited only the glomerular histopathological changes. Lipo-prostaglandin E1 at three doses significantly decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on the glomerular basement membrane in nephritic rats, but azathioprine apparently inhibited only the deposition of rat immunoglobulin G. A single administration of lipo-prostaglandin E1 inhibited the elevation of platelet aggregation and restored the decrease in renal tissue blood flow in nephritic rats. In addition, a single administration of lipo-prostaglandin E1 inhibited the elevation of glomerular thromboxane B2 and 6-keto prostaglandin F1alpha production in nephritic rats. These results suggest that lipo-prostaglandin E1 may be an effective agent for the treatment of glomerulonephritis. Its antinephritic effect may be due to the inhibition of platelet aggregation, an increase in renal tissue blood flow, a decrease in rabbit and rat immunoglobulin G deposition, and amelioration of the abnormal metabolism of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Basement Membrane; Creatinine; Glomerulonephritis, Membranous; Immunoenzyme Techniques; Kidney; Liposomes; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Thromboxane B2

Rats with streptozotocin diabetes were pair-fed diets containing 20% beef tallow (BT), fish oil (FO), or safflower oil (SO) for up to six months. After one month, differences in glucose control were not observed but rats fed FO had more renal hypertrophy. FO reduced glomerular prostaglandin E2 and 6-keto F1 alpha, and BT increased thromboxane B2 production, but there were no differences in glomerular filtration rate (GFR) or renal plasma flow (RPF). Animals fed BT needed more insulin after two months than rats fed FO followed by SO. After six months, diabetic rats fed FO had larger relative kidney weights than SO or BT, but a similar pattern was present in non-diabetic controls fed the same diets. Diabetic rats fed BT had more proteinuria than diabetic rats fed SO but not FO. However, FO-fed controls had more proteinuria than controls fed SO and similar levels of proteinuria as diabetic rats fed FO. The composition of dietary fat alters glucose tolerance in diabetic rats after two months. BT increases glomerular thromboxane production and hastens proteinuria compared to SO. FO enhances renal growth and proteinuria, but this effect is independent of the diabetic condition.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Glucose; Cattle; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dietary Fats; Dinoprostone; Fats; Fish Oils; Kidney; Kidney Cortex; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Safflower Oil; Thromboxane A2

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthase inhibitor, was evaluated using an experimental model of membranous nephropathy, viz. accelerated passive Heymann nephritis in which the glomerular injury is mediated by immune complexes. DP-1904 markedly inhibited the develop-ent of glomerular alteration as well as the elevation of proteinuria and plasma creatinine. When the treatment was started from the 22nd day, at which time proteinuria is fully developed, DP-1904 showed beneficial effects on proteinuria and glomerular histopathological changes. DP-1904 apparently decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on glomerular basement membrane in nephritic rats. A single administration of DP-1904 restored the decreased renal tissue blood flow, inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of idiopathic membranous nephropathy and that the beneficial effect of this drug may be due to the elimination of glomerular immune deposits and to an increase in renal tissue blood flow related to amelioration of the abnormal metabolism of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies; Azathioprine; Creatinine; Dinoprostone; Drug Interactions; Enzyme Inhibitors; Glomerulonephritis; Imidazoles; Immunoglobulin G; Immunosuppressive Agents; Kidney Glomerulus; Male; Methacrylates; Proteinuria; Rabbits; Rats; Rats, Sprague-Dawley; Renal Circulation; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The objective of this study was to assess the effects of flaxseed and flax oil diets in the rat renal ablation model. Flaxseed is a rich source of alpha-linolenic acid, an 18:3n3 omega-3 fatty acid, which has anti-atherogenic and anti-inflammatory properties. Flaxseed, but not flax oil, is also rich in lignans, which are platelet-activating factor-receptor antagonists. Rats were subjected to 5/6 nephrectomy, fed a regular laboratory diet (RLD) for 1 week, then divided into three groups to receive either the RLD (n = 8), a 15% flaxseed diet (n = 8), or a 15% flax oil diet (n = 7). Blood pressure, proteinuria, glomerular filtration rate, and urinary prostaglandins (thromboxane B2 and 6-keto prostaglandin F1 alpha) were measured presurgery and at 1 week (before dietary allotment) and 20 weeks postnephrectomy when blood for plasma lipids and kidneys for histology and tissue-phospholipid analyses were obtained. Blood pressure increased progressively in the RLD group but not in the flax diet groups. Plasma triglycerides and cholesterol increased in all groups, but this increase was significantly attenuated by both flax diets. Proteinuria increased 1 week postsurgery and continued to increase in the RLD group but not in the flax diet groups. Glomerular filtration rate decreased progressively, but this decline in renal function was attenuated significantly by the flax diets. Both of the flax diets prevented glomerulosclerosis and mesangial expansion. Renal alpha-linolenic acid was increased by both the flax diets (flax oil > flaxseed), but eicosapentaenoic acid increased in the flax oil group only. The flaxseed group had greater renal-arachidonic acid levels than the flax oil and RLD groups. The total omega-3 fatty acids increased twofold to threefold in the flax oil group compared with the two other groups. The total saturated fatty acids were lower and the polyunsaturated fatty acids were increased in both flax diet groups. A progressive increase in urinary thromboxane B2 occurred in the RLD group but not in the flaxseed group; the level decreased in the flax oil group. The ratio of prostaglandin F1 alpha/thromboxane B2 was preserved in the flax oil group only. In conclusion, the dietary flax seed and flax oil attenuated the decline in renal function and reduced glomerular injury with favorable effects on blood pressure, plasma lipids, and urinary prostaglandins. While we have not proven any specific synergistic effects of the constituents of the flaxseed diet,

Topics: 6-Ketoprostaglandin F1 alpha; alpha-Linolenic Acid; Analysis of Variance; Animals; Blood Pressure; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Failure, Chronic; Ligation; Linseed Oil; Lipids; Male; Nephrectomy; Plants, Edible; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Artery; Seeds; Thromboxane B2

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthetase inhibitor, was compared with that of OKY-046, using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane nephritis. Test drugs were given p.o. once daily from the day after the the development of glomerular alteration as well as the elevation of proteinuria and plasma cholesterol. On the other hand, OKY-046 (20 mg/kg per day), a thromboxane A2 synthetase inhibitor, significantly inhibited only deterioration in the glomeruli. DP-1904 and OKY-046 inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in normal and nephritic rats. Both drugs inhibited the increase in platelet aggregability, restored decreased renal tissue blood flow to a near-normal level and decreased the deposition of rat immunoglobulin G on glomerular basement membrane in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of proliferative glomerulonephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Basement Membrane; Cholesterol; Dinoprostone; Fluorescent Antibody Technique; Imidazoles; Kidney Glomerulus; Male; Methacrylates; Nephritis, Interstitial; Platelet Aggregation; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

Although the changes in prostacyclin and thromboxane A2 levels in preeclampsia have been well studied, little work has previously been done on mononuclear cells, and the cause of the changes in unclear. We determined the prostacyclin and thromboxane A2 production in mononuclear cells and investigated the effect of preeclamptic serum on this production.. The production of prostacyclin and thromboxane A2 was measured by enzyme immunoassay in 16 normal pregnant women, nine preeclamptic women with proteinuria, and six preeclamptic women without proteinuria. Sera from these three groups of women were investigated to see whether the sera have any effect on prostaglandin production.. The levels of thromboxane A2 in preeclamptic patients were found to be much higher than those of normal pregnancy, whereas the levels of prostacyclin tended to be lower. Such changes lead to a markedly increased ratio of thromboxane A2 to prostacyclin in preeclamptic patients. There was no difference in the levels of prostacyclin and thromboxane A2 between the preeclamptic patients with and without proteinuria. Serum from preeclamptic patients with proteinuria slightly reduced prostacyclin synthesis in normal pregnancy but significantly increased increased thromboxane A2 production, resulting in a ratio of thromboxane A2 to prostacyclin similar to that of preeclampsia. However, serum from preeclamptic patients without proteinuria failed to exert such effects.. The imbalance between prostacyclin and thromboxane A2 occurs in mononuclear cells from preeclamptic women, and there is a factor(s) in proteinuric-preeclamptic serum to contribute, in part, to these changes. Our findings also suggested that the cause of abnormal prostaglandin production in preeclampsia was complicated and multifactorial.

Topics: 6-Ketoprostaglandin F1 alpha; Cells, Cultured; Epoprostenol; Female; Humans; Monocytes; Osmolar Concentration; Pre-Eclampsia; Pregnancy; Proteinuria; Reference Values; Thromboxane A2

The effect of orally administered Oenothera Biennis L on chronic renal failure was studied in the partially nephrectomized rats. As compared with the control groups, the group treated with Oenothera showed the following features. 1) Urine protein excretion was reduced; 2) Level of serum cholesterol decreased; 3) Scr maintained the same level as before treatment; 4) Level of PGE1 and PGE2 increased both in renal cortex and medulla; 5) 6-keto PGF1 alpha increased in cortex; 6) Increased TXB2 production was only observed 4 weeks after nephrectomy; 7) Glomerular lesions were more severe in control group. It is concluded that Oenothera Biennis L has beneficial effect on the remnant kidney and may be useful as a kind of conservative treatment for chronic renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Dinoprostone; Drugs, Chinese Herbal; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Thromboxane B2

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 present study was conducted to investigate the antinephritic effects of berberine and coptisine, which are contained in Coptidis rhizoma, on original-type anti-GBM nephritis in rats. Berberine and coptisine at the doses of 0.5, 1.0 and 5.0 mg/kg/day, i.p. were effective in inhibiting urinary protein excretion, elevation of serum cholesterol and creatinine contents as well as glomerular histopathological changes. In addition, berberine at 20 mg/kg/day, p.o. also inhibited urinary protein excretion throughout the experimental periods. Berberine and coptisine inhibited platelet aggregation in both in vitro and in vivo assays, and berberine inhibited the decline of renal blood flow. Although berberine inhibited an increase in thromboxane B2 formation, it increased the formation of 6-keto-prostaglandin F1 alpha in platelets and isolated glomeruli. These results indicate that the antinephritic effects of berberine and coptisine may be partly due to antiplatelet action and improved renal hemodynamics via changing prostanoid synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Berberine; Cholesterol; Creatinine; Dipyridamole; Drug Evaluation, Preclinical; In Vitro Techniques; Male; Nephritis; Plant Extracts; Platelet Aggregation; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Thromboxane B2

Vasoactive eicosanoids may be involved in glomerular hyperfiltration following a high protein intake or removal of renal mass. We sequentially measured glomerular filtration rate (GFR), proteinuria (UpV), and urinary eicosanoid excretion in sham-operated (2K) and uninephrectomized (NX) rats on two diets. Compared with 12% protein (LP), 36% protein (HP) initially resulted in a higher GFR and UpV in both 2K and NX rats. Urinary excretion of 6kPGF1 alpha and TxB2 was higher on the HP diet. Ten weeks after NX, PGE2 excretion was slightly reduced, while that of TxB2 and 6kPgF1 alpha was the same as in 2K rats, indicating that the excretion per kidney had increased. From week 40, the GFR of NX rats on the HP decreased, preceded by a progressive increase in UpV. Excretion of PgE2, TxB2, and 6kPgF1 alpha was highest in the phase of proteinuric chronic renal failure. Thus, vasoactive eicosanoids are involved to maintain hyperfiltration induced by high protein intake or NX.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dietary Proteins; Eicosanoids; Glomerular Filtration Rate; Kidney; Male; Nephrectomy; Proteinuria; Random Allocation; Rats; Rats, Wistar; Thromboxane B2

The authors investigated in 19 patients with chronic proliferative glomerulonephritis the effect of 100 mg acetylsalicylic acid (ACA) administered for 12 months and the effect of 50 mg ACA administered for the same period. They evaluated the effect of the two doses on the urinary excretion of PGI and TXA2 metabolites as well as the effect on proteinuria and glomerular filtraction (GF). The authors provided evidence that small and very small amounts of ACA did not affect the excretion of the PGI metabolite, while they reduced significantly the excretion of the TXA2 metabolite and of proteinuria, and significantly increased GF.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Chronic Disease; Creatinine; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Male; Middle Aged; Proteinuria; Thromboxanes

To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 +/- 23.2 vs. 94.1 +/- 33.4 mg/day in the 16th week, p less than 0.05 and 424.4 +/- 93.3 vs. 614.4 +/- 102.3 mg/dl in the 16th week, p less than 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 +/- 29.6 vs. 288.6 +/- 46.9 nm, p less than 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Insulin; Kidney; Male; Methacrylates; Microscopy, Electron; Platelet Aggregation; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Previous studies have demonstrated that inhibition of thromboxane A2-dependent platelet aggregation by the thromboxane A2 synthase inhibitor, OKY 1581, ameliorated the progressive kidney disease of rats with subtotal renal ablation. OKY 1581 also decreased the excessive renal thromboxane A2 synthesis and lowered systemic blood pressure. In the same model, a low dose aspirin and a specific thromboxane A2 receptor antagonist failed to influence proteinuria, glomerulosclerosis, and hypertension, thus excluding a role for either platelet or renal thromboxane A2 in renal disease progression. The aims of this study were to establish (1) whether a thromboxane A2 synthase inhibitor different from OKY 1581 could retard the progression of glomerular disease in rats with remnant kidney and (2) whether this effect was associated with an increase in renal synthesis of the vasodilatory prostacyclin. Treatment of rats with renal mass ablation with FCE 22178 (100 mg/kg by gavage and 200 mg/kg in the drinking water) for 35 days starting 10 days after surgical ablation was associated with an improvement in renal function in comparison with rats receiving the vehicle alone. Proteinuria was significantly lower, and rats were partially protected from the development of glomerulosclerosis. Systolic blood pressure was significantly lower than in animals given the vehicle. Urinary thromboxane B2 excretion was significantly decreased, and urinary 6-keto-prostaglandin F1 alpha increased in respect to vehicle-treated rats. We conclude that FCE 22178 limits glomerular injury in rats with remnant kidney.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bleeding Time; Blood Pressure; Epoprostenol; Imidazoles; Kidney; Kidney Diseases; Male; Naphthalenes; Platelet Aggregation; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

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

Tumor necrosis factor (TNF) is a polypeptide hormone produced by activated macrophages detectable in the circulation of experimental animals given endotoxin. Recent evidence strongly suggests that many of the deleterious effects of endotoxin in experimental animals are mediated by TNF. Because endotoxemia in experimental animals and humans is associated with glomerular damage the present investigation was designed to establish whether TNF directly induces glomerular functional and structural changes. Twenty-three rabbits were given human recombinant TNF at the doses of 0.08, 0.8, and 8.0 micrograms/kg/h as a continuous 5-hour intravenous infusion. Animals were killed at the end of the infusion. All rabbits given 0.8 and 8.0 micrograms/kg/h TNF developed anemia (Ht value decrease at 5 hours: 0.8 microgram/kg/h, 15%; 8.0 micrograms/kg/h, 16%); leukopenia (leukocyte count decrease at 5 hours: 0.8 micrograms/kg/h, 47%; 8.0 micrograms/kg/h, 59%); thrombocytopenia (platelet count decrease at 5 hours; 0.8 micrograms/kg/h, 45%; 8.0 micrograms/kg/h, 57%). Rabbits given 8.0 micrograms/kg/h also had renal failure (serum creatinine from 1.02 +/- 0.15 to 1.64 +/- 0.34 mg/dl). By light microscopy only occasional polymorphonuclear leukocytes in the glomerular capillaries were detectable in rabbits infused with 0.08 micrograms/kg/h TNF, whereas with 0.8 micrograms/kg/h TNF the presence of inflammatory cells in the glomerular capillaries was the prominent finding. With 8.0 micrograms/kg/h TNF beside leukocyte accumulation, fibrin was detected in the glomerular capillary lumens of two of eight animals. Electron microscopy found dose-dependent glomerular endothelial cell damage in animals given TNF with fibrinlike material in the capillary lumens. Glomerular changes induced by TNF were remarkably similar to those previously found in animals given endotoxin. Thus, TNF is likely to be the mediator of endotoxin-induced glomerular damage and can be regarded as a new mediator of macrophage-dependent damage in glomerulonephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatinine; Kidney; Kidney Glomerulus; Male; Microscopy, Electron; Proteinuria; Rabbits; Regional Blood Flow; Thromboxane B2; Tumor Necrosis Factor-alpha

To determine if a selective thromboxane (TX)A2 synthetase inhibitor is clinically effective for the treatment of nephrotic syndrome, 11 patients with nephrotic syndrome were treated only with OKY-046, (E)-3-4-(1-imidazolylmethyl)phenyl-2-propenoic acid hydrochloride monohydrate, for at least 8 weeks. Urinary excretion of protein, TXB2, 2,3-dinor-TXB2, and beta-N-acetyl-D-glucosaminidase decreased with OKY-046. Creatinine clearance value, and urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), however, did not show any significant change, while serum albumin level increased. Two patients with minimal change nephrotic syndrome showed complete remission only with OKY-046. These results demonstrate that the selective TXA2 synthetase inhibitor is an effective drug for the treatment of chronic glomerulonephritis accompanied by nephrotic syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Adolescent; Adult; Aged; Female; Glomerulonephritis; Humans; Male; Methacrylates; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Proteinuria; Thromboxane B2; Thromboxane-A Synthase

One hundred NZB/W F1 female mice were studied to compare the effects of a thromboxane synthase inhibitor (TSI), a stable prostacyclin analog (iloprost) and prostaglandin E1 (PGE1) in the evolution of the nephritis. At 10 weeks of age mice were randomly assigned to cohorts of 20 to receive either no treatment, vehicle control, PGE1, iloprost or TSI. Proteinuria, mortality, systemic blood pressure, renal immune complex deposition, urinary TX B2 and 6 keto PGF1 alpha levels were measured. Mice receiving PGE1 and iloprost had a significant delay in the onset of proteinuria and reduction in mortality at 40 weeks. The TSI treatment had no apparent effect on proteinuria or mortality. The amelioration of the nephritis was not associated with an alteration in immune complex deposition in survivors at 40 weeks. Although PGE1 and iloprost lessened the age related increase in urinary TX B2, increased the urinary 6 keto PGF1 alpha levels and the ratio of 6 keto PGF1 alpha to TX B2; so did the TSI. The PGE1 treated mice did experience a marked and persistent reduction in blood pressure but this was not observed in the iloprost- or the TSI-treated mice. All drugs tested reduced the age-related increase in thromboxane B2 but only the PGE1 and iloprost had a significant effect on the evolution of the nephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Age Factors; Alprostadil; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epoprostenol; Female; Iloprost; Lupus Nephritis; Mice; Mice, Inbred NZB; Mice, Inbred Strains; Nephritis; Proteinuria; Thromboxane B2; Vasodilator Agents

Repeated subcutaneous (SC) injections of mercuric chloride (MC) in Brown Norway (BN) rats induce an autoimmune glomerulonephritis (GN) due to antiglomerular basement membrane (BM) antibody deposition in the glomeruli. The aim of this study was to investigate the effects on MC-induced autoimmune GN of OKY-046, a selective TXA-synthetase inhibitor herring oil (HO), which is rich in eicosapentaenoic acid (EPA) (5.6%) precursor of the three series of prostaglandins (PGs) and of (inactive) thromboxane (TXA3), and evening primrose oil (EPO), which is rich in linoleic acid (LA) (72%) and gamma-linolenic acid (GLNA) (9%), precursors of the one series of PGs, mainly PGE1, and of (inactive) TXA1. The administration of OKY-046 significantly inhibited proteinuria, partially prevented fibrin thrombi (FT) formation in the glomeruli, decreased urinary TXB, enhanced 6ketoPGF excretion and, increased survival rate of the animals from 60% (group receiving only MC) to 86%. However, OKY-046 did not prevent body weight (BW) loss or the development and deposition of IgG in the glomeruli. Increased intake of HO (80 days prior and throughout the experiment) and avoidance of arachidonic acid (AA) intake produced an effect comparable to that of OKY-046 in the rats. Furthermore, HO significantly inhibited the deposition of IgG in the glomeruli, increased the survival rate of the animals to 100% and further enhanced the increased urinary PGE excretion induced by MC. However, HO did not prevent BW loss in the animals. Increased intake of EPO and avoidance of AA intake produced an effect comparable to that of HO. Additionally, EPO completely prevented BW loss induced by MC in these animals. These findings suggest that the metabolites of AA, EPA and GLNA play an important role either in the development or in the modulation of this model of MC induced GN.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Autoimmune Diseases; Fatty Acids, Essential; Fatty Acids, Unsaturated; Fish Oils; gamma-Linolenic Acid; Glomerulonephritis; Hypolipidemic Agents; Immunoglobulin G; Linoleic Acids; Mercuric Chloride; Methacrylates; Oenothera biennis; Plant Oils; Prostaglandins E; Proteinuria; Rats; Thromboxane-A Synthase; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Male; Nephrotic Syndrome; Proteinuria; Puromycin; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains; Serum Albumin