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

Abstract

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.

• Authors: Katarína Sebeková, Timo Eifert, André Klassen, August Heidland, Kerstin Amann
• Journal: Diabetes (Diabetes) Vol. 56 Issue 4 Pg. 968-74 (Apr 2007) ISSN: 0012-1797 [Print] United States
• PMID: 17267764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Naphthalenes
• Propionates
• Receptors, Thromboxane
• terutroban

Topics

• Animals
• Blood Pressure
• Body Weight
• Capillaries (pathology)
• Diabetes Mellitus, Type 2 (pathology, physiopathology)
• Diabetic Nephropathies (drug therapy, pathology, physiopathology)
• Disease Models, Animal
• Kidney Glomerulus (anatomy & histology, pathology, physiopathology)
• Male
• Naphthalenes (therapeutic use)
• Nephrectomy
• Organ Size
• Propionates (therapeutic use)
• Rats
• Receptors, Thromboxane (antagonists & inhibitors)
• Renal Circulation