Effects of KW-3635, a Specific Thromboxane A2-Receptor Antagonist, on the Development of Lupus Nephritis in NZB × NZW F1 Mice

Kawakage, Michiyo; Mizumoto, Hideaki; Nukui, Etsuko; Sato, Soichiro; Karasawa, Akira

doi:10.1254/jjp.63.433

Cited by 6 publications

(3 citation statements)

References 22 publications

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“…It is, therefore, possible that the high dose of KW-3635 might have completely inhibited even the beneficial action of TXA2 in the kidney, resulting in the bell-shaped effect of KW-3635. The present results are in accordance with our previous observation that chronic administration of KW-3635 (30 mg/kg/day) markedly attenuated the lupus nephritis in NZB X NZW F1 mice, whereas the high dose (100 mg/kg/day) of this drug did not improve the nephri tis (10).…”

Section: Introductionsupporting

confidence: 93%

Protective Effect of KW-3635, a Specific Thromboxane A2-Receptor Antagonist, on Experimental Glomerulonephritis in Mice.

Kawakage¹,

Satô

Karasawa³

1994

Jpn.J.Pharmacol

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ABSTRACT-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 administra tion 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. Keywords:Thromboxane A2-receptor antagonist, Nephritis Immune glomerulonephritis has been characterized by proteinuria and changes of the renal function in many animal models. Many mediators have been reported to play roles in the progression of pathophysiologic changes following the immunologic insult (1). In the kidney, thromboxane A2 (TXA2) exerts multiple actions, such as vasoconstriction, contraction of glomerular mesangial cells and intraglomerular platelet aggregation, which may contribute to the progression of immune-mediated renal disease (2). Increased renal TXA2 biosynthesis has been documented in nephrotoxic serum (NTS) nephritis in rats, suggesting that TXA2 is an important mediator of the renal damage (3). Moreover, treatment with a TXA2 synthetase inhibitor is reported to be beneficial in the established glomerulonephritis in dogs (4). In the present study, we determined the effect of KW-3635, sodium (E) 11 [2-(5 , 6-dimethyl l -benzimidazolyl)-ethylidene]-6,11-di hydrodibenz[b,e]oxepin-2-carboxylate monohydrate, a specific TXA2 receptor antagonist (5), on glomerulo nephritis in mice to clarify the role of TXA2.Male ddY mice weighing 18 to 20 g (Shizuoka Labora tory Animal Center, Inc., Hamamatsu) were used. Food and water were provided ad libitum. NTS was produced in rabbits by repeated immunization with glomerular base ment membrane (GBM)-rich fractions according to the previously reported method (6, 7). Mice were immunized by an intraperitoneal injection of 0.5 mg rabbit IgG (RGG) emulsified with 0.25 ml of Freund complete ad juvant. Five days later, NTS in a volume of 0.075 ml was injected intravenously (day 0). The urine was collected for 6 hr under a saline load (50 ml/kg, p.o.) on days 3, 5, 10, 15, 20, 24 and 26, and the blood samples were collect ed on day 26. The amount of urinary total protein (TP) and albumin (ALB), serum ALB, total cholesterol (T-CHO) and urea nitrogen (UN) were measured by an autoanalyzer (AU510; Olympus, Tokyo). Pathological changes in the kidney slices on day 26 were evaluated af ter staining with hematoxylin and eosin. The thickening of GBM and the proliferation of mesangial cells were graded on a scale from 0 to 4+, where 0 indicated no abnormality, and 1 +, 2 +, 3 + and 4 + represented mild, moderate, moderately-severe and severe changes, respec tively. As an index of the severity of renal abnormalit...

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Section: Introductionsupporting

confidence: 93%

Protective Effect of KW-3635, a Specific Thromboxane A2-Receptor Antagonist, on Experimental Glomerulonephritis in Mice.

Kawakage¹,

Satô

Karasawa³

1994

Jpn.J.Pharmacol

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“…A TXA2 synthase inhibitor and a TXA2 receptor antagonist exerted an anti-nephritic effect on experimental nephritis in rats and a mouse lupus nephritic model, respectively (14)(15)(16). We reported that DP-1904, a TXA2 synthase inhibitor, improved the clini cal manifestations, although the treatment with DP-1904 was started after the nephritis had been established (17).…”

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confidence: 99%

Thromboxane A2 Interferes with a Disposal Process of Aggregated Protein in Glomeruli

Nagamatsu

Nagao

Nomura

et al. 1997

Japanese Journal of Pharmacology

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ABSTRACT-Immune complexes in glomeruli are involved in development of diverse glomerulonephritis. The disposal process of glomerular immune complexes has been unclarified. The present studies were un dertaken to determine if thromboxane A2 (TXA2) is associated with the disposal of macromolecules in the glomeruli using mice injected with aggregated bovine serum albumin (a-BSA). A-BSA promptly accumu lated in the glomeruli, the level reaching a plateau at 6 hr after the injection of a-BSA, and then decreased by 48 hr. The production of glomerular TXA2, prostaglandin E2 (PGE2) and prostaglandin 12 concomitantly increased with the decrease of a-BSA in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor an tagonists accelerated clearance of glomerular a-BSA without enhancing renal tissue blood flow. They did not affect a-BSA level in the plasma. In contrast, aminophylline, dopamine and mannitol significantly in creased renal tissue blood flow, but did not decrease glomerular a-BSA. TXA2 synthase inhibitors decreased TXA2 production in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists did not influence the generation of PGE2. The TXA2 analogue U-46619 significantly increased the accumulation of a-BSA in the glomeruli. We propose that TXA2 interferes with the disposal process of aggregated protein in the glomeruli. We also postulate that interception of glomerular activity of TXA2 may be an effective inter vention for managing immune complex-mediated glomerulonephritis and glomerulosclerosis.

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“…A number of studies in animal models and in man published during the last 25 years have demon strated that TP-receptor antagonists and TS inhibitors reduce albuminuria and/or proteinuria, as well as urinary excretion of TxB 2 , the stable metabolite of TxA 2 [49,56, [63][64][65][66][67][68][69][70]. Therefore, antagonizing TP receptors and/or inhibiting TS may have the potential to be beneficial in proteinuric renal diseases.…”

Section: Role Of Txa 2 In Renal Proteinuriamentioning

confidence: 99%

Effect of Pharmaceutical Interventions Targeting Thromboxane Receptors and Thromboxane Synthase in Cardiovascular and Renal Diseases

Sakariassen¹,

Alberts

Fontana

et al. 2009

Future Cardiol.

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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.

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Effects of KW-3635, a Specific Thromboxane A2-Receptor Antagonist, on the Development of Lupus Nephritis in NZB × NZW F1 Mice

Cited by 6 publications

References 22 publications

Protective Effect of KW-3635, a Specific Thromboxane A2-Receptor Antagonist, on Experimental Glomerulonephritis in Mice.

Protective Effect of KW-3635, a Specific Thromboxane A2-Receptor Antagonist, on Experimental Glomerulonephritis in Mice.

Thromboxane A2 Interferes with a Disposal Process of Aggregated Protein in Glomeruli

Effect of Pharmaceutical Interventions Targeting Thromboxane Receptors and Thromboxane Synthase in Cardiovascular and Renal Diseases

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