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NDT Advance Access originally published online on October 28, 2007
Nephrology Dialysis Transplantation 2008 23(4):1166-1172; doi:10.1093/ndt/gfm715
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model

Shuichi Ohtomo1, Masaomi Nangaku2, Yuko Izuhara1, Shunya Takizawa1, Charles van Ypersele de Strihou3 and Toshio Miyata1,4

1 Institute of Medical Sciences, Tokai University, Kanagawa, Japan 2 Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan 3 Service de Nephrologie, Universite Catholique de Louvain, Brussels, Belgium 4 Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Kanagawa, Japan

Toshio Miyata, Institute of Medical Sciences and Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Isehara, Kanagawa 259–1193, Japan. Tel: +81-463-93-1936; Fax: +81-463-93-1938; E-mail: t-miyata{at}is.icc.u-tokai.ac.jp



  Abstract

Background. Chronic renal hypoxia is suspected to play a pathogenic role in the genesis of diabetic nephropathy (DN). Cobalt enhances the activity of the hypoxia-inducible factor (HIF), a key factor in the defence against hypoxia. Its long-term effect on DN is evaluated.

Methods. Cobalt chloride was given to hypertensive, type 2 diabetic rats with nephropathy (SHR/NDmcr-cp). Treatment was initiated at the age of 13 weeks and continued for 26 weeks.

Results. Cobalt did not correct hypertension and metabolic abnormalities (obesity, hyperglycaemia and hyperlipidaemia) but reduced proteinuria as well as histological kidney injury. Cobalt upregulated renal HIF-1alpha and HIF-2alpha expression and increased the expression of HIF-regulated genes, including erythropoietin, vascular endothelial growth factor and heme oxygenase-1. The renal expression of transforming growth factor (TGF)-beta and connective tissue growth factor (CTGF) was significantly reduced by cobalt. The renal expression of NADPH oxidase, a marker of oxidative stress, and the renal content of pentosidine, a marker of advanced glycation, were also significantly reduced by cobalt.

Conclusions. Cobalt achieved renal protection independently of metabolic status and blood pressure. Its effect was attributed to the upregulation of HIF and HIF-regulated genes and to a mitigated advanced glycation and oxidative stress.

Keywords: chronic hypoxia; cobalt chloride; diabetic nephropathy; hypoxia inducible factor; oxidative stress

Received for publication: 16. 4.07
Accepted in revised form: 13. 9.07


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