Renal effects of S18886 (Terutroban), a TP receptor antagonist, in an experimental model of type 2 diabetes.
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.
Sebeková
Katarína
K
Slovak Medical University, Department of Clinical and Experimental Pharmacotherapy, Limbová 12, 83303 Bratislava, Slovakia. katarina.sebekova@szu.sk
Eifert
Timo
T
Klassen
André
A
Heidland
August
A
Amann
Kerstin
K
D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D002196:Capillaries / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D007678:Kidney Glomerulus / Q000033:anatomy & histology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D009392:Nephrectomy; D009929:Organ Size; D011422:Propionates / Q000627:therapeutic use*; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012079:Renal Circulation
D009281:Naphthalenes; D011422:Propionates; D017482:Receptors, Thromboxane; C501362:terutroban