The Thromboxane Receptor Antagonist S18886 Attenuates Renal Oxidant Stress and Proteinuria in Diabetic Apolipoprotein E-Deficient Mice
- Shanqin Xu1,
- Bingbing Jiang1,
- Karlene A. Maitland1,
- Hossein Bayat1,
- Jiali Gu2,
- Jerry L. Nadler2,
- Stefano Corda3,
- Gilbert Lavielle4,
- Tony J. Verbeuren5,
- Adriana Zuccollo1 and
- Richard A. Cohen1
- 1Vascular Biology Unit, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
- 2Department of Diabetes and Endocrinology, University of Virginia, Charlottesville, Virginia
- 3Institut de Recherches Internationales Servier, Courbevoie, France
- 4Division of Chemistry, Institut de Recherches Servier, Croissy, France
- 5Division of Angiology, Institut de Recherches Servier, Suresnes, France
- Address correspondence and reprint requests to Dr. Richard A. Cohen, Director, Vascular Biology Unit, Boston University Medical Center, 650 Albany St., X704, Boston, MA 02118. E-mail: racohen{at}bu.edu
Abstract
Arachidonic acid metabolites, some of which may activate thromboxane A2 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 S18886 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 S18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese superoxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by S18886 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. S18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, S18886 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.
- ApoE, apolipoprotein E
- COX, cyclooxygenase
- ELISA, enzyme-linked immunosorbent assay
- HETE, hydroxyeicosatetraenoic acid
- iNOS, inducible nitric oxide synthase
- PG, prostaglandin
- SOD, superoxide dismutase
- STZ, streptozotocin
- TGF-β, transforming growth factor-β
- TPr, thromboxane A2 receptor
- TX, thromboxane
Footnotes
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S.X. and B.J. contributed equally to this study.
S.X., B.J., K.A.M., H.B., and A.Z. perform work that is supported by research funds from the Institut de Recherche Servier. R.A.C. performs research supported by and receives consulting fees from the Institut de Recherche Servier.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted October 5, 2005.
- Received June 30, 2005.
- DIABETES
