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Spironolactone improves endothelial dysfunction in streptozotocin-induced diabetic rats

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An Erratum to this article was published on 30 March 2016

Abstract

Endothelial dysfunction is a critical initiator for developing diabetic vascular complications. Substantial clinical and experimental evidence suggests that aldosterone plays a crucial role in its pathogenesis. The present study aimed to investigate the effect of the mineralocorticoid receptor (MR) blocker, spironolactone, on diabetes-associated endothelial dysfunction and address the underlying mechanism(s) involved in this setting. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) to rats and spironolactone was orally administered (50 mg/kg/day). Our results showed a marked increase in aortic malondialdehyde (MDA) level and upregulation of the catalytic NADPH oxidase subunit, NOX2 gene expression alongside reducing catalase enzyme capacity, and the serum nitric oxide (NO) bioavailability in diabetic rats. This was associated with a significant reduction in endothelial nitric oxide synthase (eNOS) immunoreactivity and gene expression in diabetic aorta. The transforming growth factor-β (TGF-β) protein and the MR gene expression levels were significantly increased in the diabetic rat aorta. Moreover, the diabetic aorta showed a marked impairment in acetylcholine-mediated endothelium-dependent relaxation. Additionally, spironolactone significantly inhibited the elevated MDA, TGF-β, NOX2, and MR levels alongside correcting the dysregulated eNOS expression and the defective antioxidant function as well as NO bioavailability. Spironolactone markedly reversed the impaired endothelial function in the diabetic aorta. Collectively, our study demonstrates that spironolactone ameliorated the vascular dysfunction of diabetic aorta, at least partially via its anti-inflammatory and anti-oxidative effects alongside correcting the dysregulated eNOS and TGF-β expression. Thus, blockade of MR may represent a useful therapeutic approach against diabetic vasculopathy.

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Acknowledgments

We are grateful to Prof. Adel M. Bakeer, Professor of Pathology, Faculty of Veterinary Medicine, Cairo University, for his kind help in performing histopathological studies and interpretation of the results. We also thank Prof. Laila A. Rashed, Department of Medical Biochemistry, Unit of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, for her technical support in performing RT-PCR experiments.

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  1. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Minia University, Minia, 61511, Egypt

    Heba Adel, Ashraf Taye & Mohamed M. A. Khalifa

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  1. Heba Adel
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  2. Ashraf Taye
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  3. Mohamed M. A. Khalifa
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Correspondence to Ashraf Taye.

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Adel, H., Taye, A. & Khalifa, M.M.A. Spironolactone improves endothelial dysfunction in streptozotocin-induced diabetic rats. Naunyn-Schmiedeberg's Arch Pharmacol 387, 1187–1197 (2014). https://doi.org/10.1007/s00210-014-1048-3

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