Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the role of thromboxane A2 (TxA2) in murine lupus, we assessed the effects of the specific thromboxane receptor antagonist GR32191 on immune complex glomerulonephritis in MRL-lpr/lpr mice. Forty mg/kg/day GR32191 was given by twice daily subcutaneous injection for eight weeks beginning at 12 weeks of age. This dose completely blocked the renal vasoconstriction produced by the thromboxane agonist U46619. After eight weeks of treatment, both glomerular filtration rate (GFR) (8.9 +/- 0.6 vs. 6.8 +/- 1.1 ml/min/kg; P less than 0.05) and PAH clearance (CPAH) (37.4 +/- 2.5 vs. 29.9 +/- 3.3 ml/min/kg; P less than 0.05) were significantly higher in mice given GR32191 compared to vehicle treated animals. Administration of GR32191 also reduced proteinuria from 18.1 +/- 11.6 to 3.7 +/- 1.3 mg/24 hours (P less than 0.05). In GR32191 treated MRL-lpr/lpr mice, renal hemodynamic function and proteinuria were not significantly different from congenic MRL-+/+ controls. Thromboxane receptor blockade had striking affects on renal histomorphology reducing both hyaline thrombi in glomeruli (P = 0.022) and interstitial inflammation (P = 0.006). Glomerular crescents and severity of vasculitis also tended to be reduced in mice receiving the thromboxane receptor antagonist. The overall histopathologic score in mice given GR32191 was significantly lower than vehicle treated animals (4.7 +/- 0.5 vs. 8.4 +/- 1.5; P = 0.016). These effects of GR32191 were associated with decreased excretion of thromboxane B2 (TxB2) in urine (292 +/- 37 vs. 747 +/- 155 pg/24 hr; P less than 0.005) as well as a modest reduction in glomerular deposits of IgG (semiquantitative score 2.6 +/- 0.2 vs. 3.5 +/- 0.2; P less than 0.02). Thus, chronic thromboxane receptor blockade markedly altered the course of renal disease in MRL-lpr/lpr mice, suggesting that TxA2 is an important mediator of renal dysfunction and injury in this murine model of lupus nephritis.
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PMID:Thromboxane receptor blockade reduces renal injury in murine lupus nephritis. 138 35

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.
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PMID:Involvement of thromboxane A2, leukotrienes and free radicals in puromycin nephrosis in rats. 206 8

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.
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PMID:Effect of thromboxane synthesis inhibition in a model of membranous nephropathy. 270 63

Thromboxane (TX) A2 is a potent vasoconstrictor as well as a proaggregator of platelets. Augmented TXB2 platelet synthesis and attenuated vascular prostacyclin formation have been demonstrated in diabetes mellitus. We undertook to establish a simple method of extracting urinary TXB2 (UTXB2) and to elucidate the pathophysiologic role of renal TXA2 in diabetes mellitus. One-step extraction of UTXB2 with an octadecylsilyl-silica column was sufficient as pretreatment for TXB2 radioimmunoassay because recovery of UTXB2 was good, the eluate was parallel with the dose-response curve, and the value coincided with that obtained by the conventional method. When platelet TXA2 synthesis was completely suppressed by administration of 100 mg aspirin, urinary TXB2 excretion (UTXB2V) declined to 41% of the initial levels, suggesting that renal TXA2 formation contributes significantly to UTXB2V. UTXB2V was 94.5 +/- 14.0 ng/day or 108.8 +/- 17.3 ng/gm creatinine in controls. Approximately half of the patients with diabetes demonstrated a UTXB2 level higher than the mean + 2 SD level of controls. Although UTXB2V did not show a significant correlation with protein excretion, UTXB2V in patients with diabetes with proteinuria greater than 100 mg/day was augmented (224.4 +/- 30.5 ng/day) compared with that in patients with diabetes without proteinuria greater than 100 mg/day. Furthermore, UTXB2V correlated negatively with the p-aminohippuric acid clearance rate, but not with the creatinine clearance rate. The results suggest that renal TXA2 synthesis may be augmented in diabetic nephropathy and may play a pathophysiologic role in renal hemodynamics as well as in protein excretion.
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PMID:Increased thromboxane B2 excretion in diabetes mellitus. 358 44

The clinical efficiency and mechanism of traditional Chinese medicinal herb Salvia Miltiorrhizae Bge (SMB) and Ligustrazine (L) on pregnancy induced hypertension (PIH) were studied in 30 patients. Before and after the administration of SMB and L, the following parameters: mean arterial pressure (MAP), proteinuria, levels of Thromboxane A2 (TXA2) and Prostacyclin (PGI2) were observed. TXA2 and PGI2 were measured by their stable hydration products Thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by an established radioimmunoassay. The results of treatment were compared with the base line values and showed as follows: MAP and proteinuria decreased significantly (P < 0.05); no marked difference existed in TXB2; the level of 6-keto-PGF1 alpha increased significantly (P < 0.05); the rate of TXB2/6-keto-PGF1 alpha decreased significantly (P < 0.05). The results suggested that SMB and L can invigorate blood circulation by decreasing vasoconstriction.
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PMID:[The effects of Salvia miltiorrhizae Bge and Ligustrazine on thromboxane A2 and prostacyclin in pregnancy induced hypertension]. 771 82

Thromboxane A(2) (TxA(2)) is assumed to contribute to the development of diabetes complications, including nephropathy. We investigated whether the selective thromboxane-prostanoid endoperoxide receptor antagonist, S18886, ameliorates renal damage in uninephrectomized (UNX) obese Zucker rats (OZR). S18886, at doses of 10 (S18886-10) and 30 (S18886-30) mg x kg(-1) x day(-1), was administered to UNX-OZR by gavage over 8 weeks (n = 8 each group). UNX lean rats (n = 12) and OZR rats that received placebo (OZR-PLAC, n = 8) served as controls. As compared with the OZR-PLAC, S18886 had no significant effect on the elevated blood pressure and the enhanced creatinine clearance, while augmented proteinuria was partially prevented (-12 and -37%, low and high dose, respectively; NS). The increased excretion of transforming growth factor beta(1) (TGF-beta(1)) and of the thromboxane metabolite 2,3-dinor thromboxane B(2) (TxB(2)) was lowered (P < 0.05). S18886 prevented both the enhanced mesangiolysis (P < 0.01) in the OZR-PLAC as well as enlargement and degeneration of podocytes. In the blood, S18886-30 augmented the antioxidant enzymes (P < 0.01) and lessened the increase of plasma advanced oxidation protein products (-25%, NS). Body weight, hyperglycemia, and dyslipidemia remained uninfluenced under both doses of treatment. S18886 has renoprotective properties in the model of UNX-OZR. It prevents mesangiolysis, reduces urinary TGF-beta(1) and 2,3-dinor-TxB(2) excretion, and enhances the antioxidative defense.
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PMID:Renal effects of S18886 (Terutroban), a TP receptor antagonist, in an experimental model of type 2 diabetes. 1726 64