thromboxane-a2 and Proteinuria

The present review focuses on the roles of thromboxane A2 (TxA2) in arterial thrombosis, atherogenesis, vascular stent-related ischemic events and renal proteinuria. Particular emphasis is laid on therapeutic interventions targeting the TxA2 (TP) receptors and TxA2 synthase (TS), including dual TP-receptor antagonists and TS inhibitors. Their significant inhibitory efficacies on arterial thrombogenesis, atherogenesis, restenosis after stent placement, vasoconstriction and proteinuria indicate novel and improved treatments for cardiovascular and selected renal diseases. New therapeutic interventions of the TxA2 pathway may also be beneficial for patients with poor biological antiplatelet drug response, for example, to aspirin and/or clopidogrel. These new TP/TS agents offer novel improved treatments to efficiently and simultaneously interfere with thrombogenesis and atherogenesis, and to enlarge the existing panel of platelet inhibitors for efficient prophylaxis and treatment of arterial thrombosis and renal proteinuria.

Topics: Aspirin; Cardiovascular Diseases; Clopidogrel; Coronary Artery Disease; Coronary Restenosis; Humans; Kidney Diseases; Platelet Aggregation Inhibitors; Proteinuria; Receptors, Thrombin; Thrombosis; Thromboxane A2; Thromboxane-A Synthase; Ticlopidine

Cyclooxygenase inhibitors have long been used in experimental studies as well as in clinical practice to reduce urinary protein excretion in proteinuric renal diseases. However, the mechanisms by which this treatment limits glomerular filtration of proteins are not fully elucidated. We will review the cellular and molecular mechanisms that regulate glomerular permselectivity and the experimental observations available on the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on these glomerular functions. The effects of NSAIDs on glomerular microcirculation will also be analyzed in comparison with another class of drugs used to lower proteinuria in nephrotic patients, the angiotensin converting enzyme inhibitors. Finally, we will analyze the relationship between urinary prostaglandins and thromboxane A2 and discuss the effects of modulating these hormones on glomerular functions.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Glomerular Filtration Rate; Humans; Prostaglandins; Proteinuria; Thromboxane A2

Neutral endopeptidase (NEP: EC 3.4.24.11) is involved in the degradation of peptides such as atrial natriuretic peptide, angiotensin II (AngII), and endothelin-1 (ET-1). In this study we propose that NEP inhibition provides protection in glycerol-induced acute renal failure (ARF). Renal vascular responses were evaluated in ARF rats where ARF was induced by injecting 50% glycerol in candoxatril, a NEP inhibitor (30 mg/kg, orally; for 3 weeks) pretreated rats. AngII and U46619 (a TxA2 mimetic) vasoconstriction was increased (2- to 4-fold) in ARF while ET-1 vasoconstriction was surprisingly reduced (23+/-3%; p<0.05). In ARF, candoxatril paradoxically enhanced ET-1 response (60+/-20%; p<0.05) but reduced AngII vasoconstriction (51+/-11%; p<0.05) without affecting U46619 response. However, candoxatril treatment was without effect on plasma ET-1 and TxB2 levels in ARF. Candoxatril reduced plasma AngII by 34+/-4% (p<0.05) in ARF which was approximately 3.5-fold higher compared to control. Candoxatril doubled the nitrite excretion in control but was without effect on proteinuria or nitrite excretion in ARF. Candoxatril enhanced Na+ and creatinine excretion in ARF by 73+/-9% and 33+/-2%, respectively. These results suggest that NEP inhibition may confer protection in glycerol-induced ARF by stimulating renal function but without a consistent effect on renal production and renal vascular responses to endogenous vasoconstrictors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Kidney Injury; Administration, Oral; Angiotensin II; Animals; Antihypertensive Agents; Creatinine; Endothelin-1; Indans; Kidney; Male; Natriuresis; Neprilysin; Nitrates; Propionates; Proteinuria; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear transcription factor, modulates vascular responses to angiotensin II (AII) or thromboxane A(2) (TxA(2)) via regulation of their gene/receptor. Increased vasoconstriction and deteriorating renal function in glycerol-induced acute renal failure (ARF) may be attributed to down-regulation of PPARgamma. In this study, we investigated the effect of ciglitazone (CG), a PPARgamma inducer, on AII and TxA(2) production and activity in glycerol-induced ARF. Vascular responses to AII or 9,11-dideoxy-11alpha,9alpha-epoxymethano prostaglandin F(2alpha) (U46619), a TxA(2) mimetic, were determined in preglomerular vessels following induction of ARF with glycerol. Renal damage and function were assessed in CG-treated (9 nmol/kg for 21 days) rats. PPARgamma protein expression and activity, which were significantly lower in ARF rats, were enhanced by CG (26 and 30%). CG also increased PPARgamma mRNA by 67 +/- 6%, which was reduced in ARF. In ARF, there was significant tubular necrosis and apoptosis, a 5-fold increase in proteinuria and a 2-fold enhancement in vasoconstriction to AII and U46619. CG reduced proteinuria (49 +/- 3%), enhanced Na(+) (124 +/- 35%) and creatinine excretion (92 +/- 25%), markedly diminished tubular necrosis, and reduced ARF-induced increase in AII (40 +/- 3%) and TxA(2) (39 +/- 2%) production, the attending increase in vasoconstriction to AII (36 +/- 2%) and U46619 (50 +/- 11%), and the increase in angiotensin receptor-1 (AT(1)) (23 +/- 3%) or thromboxane prostaglandin (TP) receptor (13 +/- 1%). CG reduced free radical generation by 55 +/- 14% while elevating nitrite excretion (65 +/- 13%). Our results suggest that enhanced activity of AII and TxA(2), increased AT(1) or TP receptor expression, and renal injury in glycerol-induced ARF are consequent to down-regulation of PPARgamma gene. CG ameliorated glycerol-induced effects through maintaining PPARgamma gene.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Kidney Injury; Angiotensin II; Animals; Creatinine; Dinoprost; Gene Expression; Glycerol; Hypoglycemic Agents; Kidney Glomerulus; Male; Nitric Oxide; Nitrites; PPAR gamma; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Thromboxane A2, Prostaglandin H2; Renal Artery; Sodium; Thiazolidinediones; Thromboxane A2; Thromboxane B2; Vasoconstriction

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

In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement induces glomerular epithelial cell injury and proteinuria, which is partially mediated by eicosanoids. Glomerular cyclooxygenase (COX)-1 and -2 are up-regulated in PHN and contribute to prostanoid generation. In the current study, we address the role of COX isoforms in proteinuria, using the nonselective COX inhibitor indomethacin and the COX-2-selective inhibitor 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone (DFU). Four groups of rats with PHN were treated twice daily, from day 7 through 14 with vehicle, 1 mg/kg DFU, 10 mg/kg DFU, or 2 mg/kg indomethacin. Vehicle-treated rats with PHN showed significant proteinuria on day 14 (163 +/- 15 mg/d, n = 19), compared with normal rats (10 +/- 4 mg/d, n = 3, p < 0.001). Treatment with DFU (1 or 10 mg/kg) reduced proteinuria significantly (by ~33%), compared with vehicle, but to a lesser extent than indomethacin (56% reduction). Glomerular eicosanoid generation was reduced significantly in the DFU and indomethacin groups, compared with vehicle. There were no significant differences among vehicle- or DFU-treated groups in [(3)H]inulin clearance, or in glomerular expression of COX-1 and -2. DFU did not affect the autologous immune response. In cultured rat glomerular epithelial cells, COX inhibition reduced complement-induced cytotoxicity, and this reduction was reversed by the thromboxane A(2) analog 9,11-dideoxy-9alpha,11alpha-methanoepoxyprostaglandin F(2alpha) (U46619). Thus, in experimental membranous nephropathy, selective inhibition of COX-2 reduces proteinuria, without adversely affecting renal function. However, inhibition of both COX-1 and -2 is required to achieve a maximum cytoprotective and antiproteinuric effect.

Topics: Actins; Animals; Complement System Proteins; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Eicosanoids; Epithelial Cells; Furans; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis; Immunoglobulin G; Indomethacin; Isoenzymes; Male; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Proteinuria; Rats; Rats, Sprague-Dawley; 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

To clarify the role of thromboxane A2 (TxA2), endothelin-1 (ET-1) and endothelin-3 (ET-3) in the progression of glomerular injury in accelerated nephrotoxic serum nephritis (NTN) in the rat, we studied the expression of ET-1 and ET-3 at the kidney by immunohistochemical method and examined the effect of a novel TxA2 receptor antagonist, S-1452. The S-1452-treated group showed significantly lowered 24-hr proteinuria and milder glomerular cell proliferation and lobulation than the non-treated group (NT group) on experimental day 10. There was no significant difference in the glomerular polymorphonuclear cell (PMN) exudation between the 2 groups. Immunofluorescent findings revealed that ET-1 and ET-3 were seen along the glomerular capillary wall and partly in the mesangial area in all rats of the NTN group. The degree and positive rate of ET-1 and ET-3 staining were significantly higher in the NTN group than in the S-1452 group. These findings suggest that TxA2 may be an important mediator in the development of NTN, and that TxA2 receptor antagonist may be useful for the reduction of glomerular injury in this type of nephritis. In addition, local production of ET may contribute to the development of this nephritis.

Topics: Animals; Bridged Bicyclo Compounds; Chromium; Endothelin-1; Endothelin-3; Fatty Acids, Monounsaturated; Immunohistochemistry; Kidney Glomerulus; Male; Microscopy, Fluorescence; Nephritis; Prostaglandin Antagonists; Proteinuria; Rabbits; Rats; Rats, Wistar; Receptors, Thromboxane; Sodium; Thromboxane A2

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

Cyclosporine (CsA)-treated female Wistar rats, in dose of 37.5 microM (45 mg)/kg/day for 7 days, exhibited significantly decreased creatinine clearance (Ccr), and provoked body weight loss (BWL), which is consistent with the development of nephrotoxicity (NT). Urine volume (V) did not change and proteinuria (PU) was not provoked. These changes were associated with significantly diminished ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 excretions. Light-microscopic (LM) sections of rat kidneys showed that all kidneys were affected but the lesions (mainly diffuse vacuolization) were reversible. When CsA-treated animals were pretreated with ketanserine (KTS), which antagonizes (a) the direct vasoconstrictor effect of serotonin (5-HT), and (b) the amplifying effects of 5-HT on other vasoactive substances (such as noradrenaline (NA), alpha 1-receptors, histamine, H2 receptors, and prostaglandin F2 alpha), Ccr and urine volume significantly increased, BWL was partially prevented and the ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 excretions were significantly enhanced. LM sections showed that only 5 of 9 rats were affected but the lesions were of less importance. These observations indicate that the NT induced by CsA in our studies was mediated by 5-HT, a potent vasoconstrictor agent, and by the metabolites of arachidonic acid. However, other vasoactive agents and additional mechanisms could also be implicated.

Topics: Animals; Body Weight; Creatinine; Cyclosporine; Female; Immunosuppressive Agents; Ketanserin; Kidney; Prostaglandins; Proteinuria; Rats; Rats, Wistar; Serotonin Antagonists; Thromboxane A2

We studied the effect of KW-3635, a selective thromboxane A2 (TXA2)-receptor antagonist, on experimental glomerulonephritis. The glomerulonephritis was induced in mice by the administration of rabbit anti-mouse glomerular basement membrane (GBM) antibody. It was characterized as proteinuria, changes of serum biochemical parameters and glomerular histopathological abnormalities. The administration of KW-3635 (30 mg/kg/day, p.o.) significantly ameliorated the proteinuria, elevation of serum urea nitrogen and the thickening of GBM. These data suggest that TXA2 may play an important pathogenic role in the development and progression of glomerulonephritis.

Topics: Animals; Antibodies, Monoclonal; Basement Membrane; Benzimidazoles; Benzoxepins; Blood Urea Nitrogen; Disease Models, Animal; Glomerulonephritis; Kidney Glomerulus; Male; Mice; Proteinuria; Thromboxane A2

We examined the effect of KW-3635, a specific thromboxane A2 (TXA2)-receptor antagonist, on the development of lupus nephritis in NZB x NZW F1 mice. KW-3635 was orally given once a day for 33 weeks beginning at eight weeks of age. In the control group, the mice began to die at 39 weeks of age, showing severe proteinuria and histopathologic abnormality in the renal glomeruli. Administration of KW-3635 (30 mg/kg/day) significantly reduced urinary protein excretion (1.7 +/- 0.9 vs. 8.5 +/- 2.4 mg/6 hr/mouse, P < 0.01), mortality (1/18 vs. 6/19, P < 0.05) and the histopathologic score of the kidney examined at 41 weeks of age. Thus, chronic administration of KW-3635 markedly attenuated the renal disease in NZB x NZW F1 mice, suggesting that TXA2 is an important mediator of the pathogenesis in this murine model of lupus nephritis.

Topics: Administration, Oral; Animals; Antibodies, Antinuclear; Benzimidazoles; Benzoxepins; Female; Immunohistochemistry; Kidney; Lupus Nephritis; Mice; Proteinuria; Thromboxane A2

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 antiproteinuric effect of the antiplatelet agent dipyridamole has been assessed after inhibition of thromboxane B2 (TxB2) synthesis in 8 patients with confirmed membranous glomerulonephritis. There were three study periods, each of 30 days, and 45 days apart, namely a washout period, treatment with dipyridamole 300 mg/d, and dipyridamole 225 mg/d plus aspirin 150 mg/d. On Days 1 and 30 of each study period serum and urine creatinine, 24-h excretion of protein, creatinine clearance, platelet aggregometry on whole blood and serum TxB2 were measured. Treatment with dipyridamole alone or with aspirin produced significant inhibition of platelet aggregation and a fall in 24-h protein excretion; the latter amounted to 54% with dipyridamole alone and 56% with dipyridamole plus aspirin (NS). Dipyridamole plus aspirin caused an 82% reduction in serum TxB2.

Topics: Adult; Aspirin; Dipyridamole; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Kidney Function Tests; Male; Platelet Aggregation; Proteinuria; Thromboxane A2

Topics: Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Glomerular Filtration Rate; Humans; Proteinuria; Sulindac; Thromboxane A2; Thromboxane B2

Thromboxane A2 (TXA2), leukotrienes (LTs) and free radicals are considered to be possible mediators in the induction of glomerular injury and proteinuria. In this study, we examined the involvement of these three mediators and the protective effect of simultaneous inhibition of all three in puromycin aminonucleoside (PAN) nephrosis in rats. A single intraperitoneal injection of PAN (100 mg/kg) induced massive proteinuria and enhanced production of TXA2 and LTs from arachidonic acid in renal cortical slices and renal glomeruli, and increased malondialdehyde levels in plasma, urine and renal cortex. Oral administration of CV-6504(HCl) (3 to 20 mg/kg/day, for 1 to 2 weeks), a novel treble inhibitor of TXA2 synthetase, 5-lipoxygenase and lipid peroxidation, dose-dependently attenuated PAN-induced proteinuria and the increases in these three mediators. Any single specific inhibitor (CV-4151, a TXA2 synthetase inhibitor; AA-861, a 5-lipoxygenase inhibitor; or CV-3611, a radical scavenger) or a combination of two inhibitors showed no or only a slight antiproteinuric effect, but the combination of all three inhibitors significantly reduced PAN-induced proteinuria. These results suggest that, these three mediators may be involved in the pathogenesis of PAN nephrosis and that CV-6504(HCl), which can simultaneously inhibit all three, may be a useful therapeutic agent for nephrosis.

Topics: Animals; Antioxidants; Benzoquinones; Free Radicals; Kidney Cortex; Kidney Glomerulus; Leukotrienes; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Malondialdehyde; Nephrosis; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane-A Synthase

An evaluation was made of the possible relation between renal thromboxane (Tx)A2 synthesis (measured as urinary excretion of TxB2) and the loss of glomerular permeability to proteins, in 5 children with seven episodes of minimal change nephrotic syndrome. Urinary TxB2 excretion was significantly higher in children with minimal change nephrotic syndrome than in 14 healthy controls, and reached its maximum at the time of peak proteinuria. During remission of nephrotic syndrome urinary excretion of TxB2 was still significantly higher than in healthy controls. A significant positive correlation between urinary excretion of TxB2 and proteinuria was observed in 3 patients. The results suggest that renal TxA2 could be regarded as one of the possible mediators of the altered glomerular permeability to proteins in minimal change nephrotic syndrome.

Topics: Child; Female; Humans; Kidney; Male; Nephrosis, Lipoid; Proteinuria; Thromboxane A2; Thromboxane B2

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

While much is known regarding acute nephrotoxic serum (NTS)-induced glomerular injury, the glomerular dynamics and pathophysiologic mediators of the more relevant chronic autologous phase remain poorly defined. Studies were performed in rats 14 d after injection of rabbit serum (n = 6), NTS in the absence (n = 6), or presence, of a cyclooxygenase inhibitor, ibuprofen (n = 6) or a thromboxane A2 (TxA2) receptor antagonist, L-670,596 (n = 5). A mesangial macrophage/monocyte infiltrate was noted with equal intensity in all NTS-treated rats. Glomerular generation rates of prostaglandin (PG) E2, PGF2a, and TxA2 in nephritic kidneys were dramatically increased as compared to controls. 2 wk after NTS, there was an increase in glomerular plasma flow rate (SNPF), attainment of filtration pressure disequilibrium, and augmentation of net transcapillary hydraulic pressure difference (delta P). Glomerular filtration rate (GFR), however, was reduced, due to a marked fall in the glomerular capillary ultrafiltration coefficient (Kf). Cyclooxygenase inhibition resulted in normalization of glomerular eicosanoid generation rates, amelioration of proteinuria, afferent vasoconstriction, and normalization of SNPF, delta P, Kf, and GFR. Selective antagonism of TxA2 also led to preservation of Kf, but was without effect on SNPF, thereby leading to elevated values for GFR. Thus, in contrast to the pathophysiologic role of arachidonate-lipoxygenase products in the early heterologous phase, PG-mediated vasodilatation and TxA2-induced reductions in Kf and GFR underlie glomerular functional changes during autologous mesangioproliferative glomerulonephritis.

Topics: Animals; Blood Pressure; Dinoprost; Dinoprostone; Glomerular Filtration Rate; Glomerulonephritis; Hematocrit; Male; Platelet Activating Factor; Proteinuria; Rats; Thromboxane A2; Vascular Resistance

The effect of the thromboxane synthesis inhibitor UK 38485 on glomerular filtration rate (GFR) and proteinuria was evaluated in a rat model of unilateral membranous nephropathy. Two and 24 hours following perfusion of kidneys with cationized human IgG and i.v. administration of anti-human IgG-antiserum (in situ ICGN), glomerular thromboxane B2 (TxB2) formation was significantly higher (2 hr: 448 +/- 116 pg/mg protein/min; 24 hr: 173 +/- 21 pg/mg protein/min) compared to control (C) kidneys (2 hr: 173 +/- 21 pg/mg protein/min, P less than 0.005; 24 hr: 154 +/- 17 pg/mg protein/min, P less than 0.025). Two and seven days after induction of ICGN these differences were no longer present. Pretreatment with the thromboxane synthesis inhibitor UK 38485 prevented the decrease in GFR, which occurred two hours after induction of the glomerular disease (without UK: 161 +/- 31; with UK 325 +/- 21 microliters/100 g body wt/min). This UK 38485 effect on GFR was no longer detectable at 24 hours, two days and seven days. Initiation of glomerular immune injury was followed by significant proteinuria which averaged 250 +/- 85 mg/24 hr at day two. UK 38485 treatment, which reduced TxB2 formation in isolated glomeruli by 90% did not influence proteinuria. These data demonstrate that induction of heterologous, in situ immune complex glomerulonephritis stimulates glomerular thromboxane B2 formation, an effect which partially modulates the decrease in GFR at two hours. Thromboxane, however, does not seem to play a role in the mediation of proteinuria in this animal model.

Topics: Animals; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Imidazoles; Proteinuria; Rats; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Time Factors

Platelets have been implicated as mediators of mesangial cell proliferation. Of interest is a potential role for platelet secretory proteins (some of which are known to be growth factors) in proliferative glomerular disease. This study examines the effect of sulindac, an inhibitor of platelet thromboxane A2 generation and platelet activation, on the development of glomerular cystic and proliferative lesions after injection of habu snake venom (HSV). To examine the association of platelet secretory proteins with glomerular lesions after HSV, antiserum against a pool of platelet secretory cationic proteins (PSCPs) was used, by immunofluorescence, as a marker of the secretory component of platelet activation in platelet-compromised and normal rats. Uninephrectomized rats received sulindac (60 mg/kg body weight) or vehicle daily before and after HSV (2 mg/kg body weight, IV). Glomerular cysts, proliferative nodules, and mixed lesions (cystic plus proliferative) were quantitated and PSCP localization was examined 48 hours after HSV. Sulindac substantially reduced the total number of glomerular lesions and preferentially reduced proliferative lesions when compared with controls. PSCPs localized in glomerular lesions in both groups and paralleled the severity of disease, but overall intensity of PSCP staining was less in sulindac-treated rats. Sulindac did not alter renal function before HSV, ruling out hemodynamic factors. The concomitant localization of PSCPs in glomerular lesions and amelioration by antiplatelet therapy supports a role for platelet secretory proteins in this model of proliferative glomerular disease.

Topics: Animals; Blood Platelets; Blood Proteins; Blood Urea Nitrogen; Cations; Crotalid Venoms; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis; Male; Platelet Aggregation Inhibitors; Proteinuria; Rats; Rats, Inbred Strains; Sulindac; Thromboxane A2

Topics: Animals; Blood Pressure; Diabetes Mellitus, Experimental; Kidney; Male; Methacrylates; Proteinuria; Rats; Rats, Inbred Strains; Renin; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Topics: Animals; Indoles; Male; Nephrotic Syndrome; Piperazines; Platelet Activating Factor; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains; Thromboxane A2