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Diabetes Publish Ahead of Print published online ahead of print January 31, 2007
DOI: 10.2337/db06-1136
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Original Research

Renal effects of S18886 (terutroban), a TP receptor antagonist, in an experimental model of type 2 diabetes

Katarína Sebeková1, Timo Eifert2, André Klassen3, August Heidland3, and Kerstin Amann2

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

Correspondence: katarina.sebekova{at}szu.sk

Key Words: selective thromboxane-prostanoid endoperoxide (TP) receptor antagonist -- diabetic nephropathy -- proteinuria -- mesangiolysis -- glomerulosclerosis

Thromboxane A2 (TxA2) is assumed to contribute to the development of diabetic 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/d, was administered to UNX-OZR by gavage over 8 weeks (n=8 each group). UNX lean rats (n=12) and OZR, receiving placebo OZR-PLAC (n=8), served as controls.

As compared to 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, n.s.). 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%, n.s.). 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 defence.


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