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- Title
The Thromboxane Receptor Antagonist S18886 Attenuates Renal Oxidant Stress and Proteinuria in Diabetic Apolipoprotein E--Deficient Mice.
- Authors
Shanqin Xu; Jiang, Bingbing; Maitland, Karlene A.; Bayat, Hossein; Gu, Jiali; Nadler, Jerry L.; Corda, Stefano; Lavielle, Gilbert; Verbeuren, Tony J.; Zuccollo, Adriana; Cohen, Richard A.
- Abstract
Arachidonic acid metabolites, some of which may activate thromboxane A[sub 2] receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with $18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E-/- mice. Diabetic mice were treated with S18886 (5 mg ⋅ kg-1 ⋅ day-1) or aspirin (30 mg ⋅ kg-1 ⋅ day-1) for 6 weeks. Neither $18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese super-oxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by $18886 but not by aspirin. Staining for the NADPH oxidase subunit p47phox, inducible nitric oxide synthase, and 12-lipoxygenase was increased in diabetic mouse kidney, as were urine levels of 12-hydroxyeicosatetraenoic acid and 8-iso-prostaglandin F2α. $18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, $18886 significantly attenuated microalbuminuria in diabetic mice and ameliorated histological evidence of diabetic nephropathy, including transforming growth factor-β and extracellular matrix expression. Thus, in contrast to inhibiting cyclooxygenase, blockade of TPr may have therapeutic potential in diabetic nephropathy, in part by attenuating oxidative stress.
- Subjects
ARACHIDONIC acid; METABOLITES; THROMBOXANES; DIABETES complications; CYCLOOXYGENASES
- Publication
Diabetes, 2006, Vol 55, Issue 1, p110
- ISSN
0012-1797
- Publication type
Article