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Renal Effects of S18886 (Terutroban), a TP Receptor Antagonist, in an Experimental Model of Type 2 Diabetes

Katarína ebeková¹, Timo Eifert², André Klassen³, August Heidland³, and Kerstin Amann²

¹ Slovak Medical University, Department of Clinical and Experimental Pharmacotherapy, Bratislava, Slovakia
² Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany
³ Department of Internal Medicine, University of Würzburg, Würzburg, Germany

Address correspondence and reprint requests to Katarína ebeková MD, DSc, Slovak Medical University, Department of Clinical and Experimental Pharmacotherapy, Limbová 12, 833 03 Bratislava, Slovakia. E-mail: katarina.sebekova{at}szu.sk

Abbreviations: AOPP, advanced oxidation protein product; apoE, apolipoprotein E; AST, aspartate-aminotransferase; AT II, angiotensin II; GN, glomerulonephritis; GPX, glutathione peroxidase; GSI, glomerulosclerosis index; HE, hematoxylin/eosin; HETE, 12-hydroxyeicosatatraenoic acid; HMG-CoA, 3-hydroxymethyl-glutaryl-coenzyme A; LZR, lean Zucker rat; MGI, mesangiolysis index; OZR, obese Zucker rat; PAS, periodic Schiff's acid; PLAC, placebo; PG, prostaglandin; SOD, superoxide dismutase; STZ, streptozotocin; TGF-ß₁, transforming growth factor ß₁; TP, thromboxane-prostanoid endoperoxides; TxA₂, thromboxane A₂; TxB₂, thromboxane B₂; UNX, uninephrectomy; WBC, white blood cell

Thromboxane A₂ (TxA₂) 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 · kg^–1 · 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 ß₁ (TGF-ß₁) and of the thromboxane metabolite 2,3-dinor thromboxane B₂ (TxB₂) 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-ß₁ and 2,3-dinor-TxB₂ excretion, and enhances the antioxidative defense.

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