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NDT Advance Access originally published online on March 14, 2007
Nephrology Dialysis Transplantation 2007 22(6):1547-1557; doi:10.1093/ndt/gfm099
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Overexpression of thioredoxin1 in transgenic mice suppresses development of diabetic nephropathy

Yasuhiro Hamada1, Satoshi Miyata1, Tomoko Nii-Kono1, Riko Kitazawa2, Sohei Kitazawa2, Satomi Higo1, Michiru Fukunaga1, Shigemitu Ueyama1, Hajime Nakamura3, Junji Yodoi4, Masafumi Fukagawa1 and Masato Kasuga1

1Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, 2Division of Molecular Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Kobe, 3Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital and 4Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan

Correspondence and offprint requests to: Satoshi Miyata, Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Email: miyata{at}med.kobe-u.ac.jp



  Abstract

Background. Oxidative stress has been suggested to play an important role in the pathogenesis of diabetic nephropathy. In the present study, the effects of thioredoxin1 (TRX1) overexpression, a small protein with antioxidant property, on the development of diabetic nephropathy in streptozotocin-induced diabetic animals were investigated using TRX1 transgenic mice (TRX1-Tg).

Methods. Eight-week-old male TRX1-Tg and wild-type mice littermates (WT) mice were treated either with streptozotocin (200 mg/kg) or vehicle alone. After 24 weeks of treatment, diabetic nephropathy and oxidative stress were assessed in these four groups of mice, by biochemical analyses of blood and urine, as well as by histological analyses of the kidneys.

Results. Haemoglobin A1c (HbA1c) levels of diabetic TRX1-Tg were not significantly different from those of the diabetic WT. Nevertheless, an augmented urinary albumin excretion observed in diabetic WT was significantly diminished in diabetic TRX1-Tg. Histological study revealed that pathological changes such as mesangial matrix expansion and tubular injury were significantly prevented in diabetic TRX1-Tg accompanied by a reduced tendency of expression of transforming growth factor-ß as compared with diabetic WT. In parallel, urinary excretion of 8-hydroxy-2'-deoxyguanosine and acrolein adduct and the immunostaining intensities of these markers in the kidney were significantly higher in diabetic WT compared with non-diabetic mice. The markers were significantly suppressed in diabetic TRX1-Tg, an indication of systemic and renal oxidative stress attenuation by TRX1 overexpression.

Conclusion. These findings indicated the significant role of oxidative stress in the development of diabetic nephropathy and a potential inhibition of progression of nephropathy by TRX1.

Keywords: diabetic nephropathy; oxidative stress; thioredoxin1

Received for publication: 18. 5.06
Accepted in revised form: 5. 2.07


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