Activation of hypoxia-inducible factor by cobalt is associated with the attenuation of tissue injury and apoptosis in cyclosporine-induced nephropathy
- Authors
- Oh S.W.; Ahn J.M.; Lee Y.-M.; Kim S.; Chin H.J.; Chae D.-W.; Na K.Y.
- Issue Date
- 2012
- Keywords
- Apoptosis; Cyclosporine; Fibrosis; Hypoxia-inducible factor 1; Inflammation
- Citation
- Tohoku Journal of Experimental Medicine, v.226, no.3, pp 197 - 206
- Pages
- 10
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- Tohoku Journal of Experimental Medicine
- Volume
- 226
- Number
- 3
- Start Page
- 197
- End Page
- 206
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/12800
- DOI
- 10.1620/tjem.226.197
- ISSN
- 0040-8727
1349-3329
- Abstract
- Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses. Despite the therapeutic benefits of cyclosporine A (CsA) in organ transplantation, its clinical use is limited due to chronic nephropathy. We investigated whether HIF activation by cobalt could improve CsA-induced nephropathy, and investigated the related mechanism. In animal experiments, rats were kept on a 0.05% low-salt diet and administered CsA subcutaneously for 28 days (15 mg/kg/day). They also received cobalt (10 mg/kg/day) during the entire experimental period. The administration of cobalt significantly increased HIF-1α expression in the kidney. The increased expression of HIF-1α ameliorated CsA-induced afferent arteriolopathy and tubulointerstitial injury in the kidney. Cobalt significantly reduced the infiltration of macrophages/monocytes into the renal tubulointerstitium. In addition, HIF activation by cobalt reduced the number of CsA-induced apoptotic cells in the kidney. Subsequently, HK-2 human renal tubular epithelial cells were used for in vitro experiments. They were pre-treated with 150 μM of cobalt to activate HIF, and then exposed to 10 μM CsA. HIF activation by cobalt decreased the CsA-induced apoptosis in HK-2 cells, as judged by the decreases in the number of apoptotic cells, pro-apoptotic caspase-3 activity, and the expression level of cleaved caspase-3, together with the increase in the expression of anti-apoptotic bcl-2. Cobalt pretreatment also reduced the CsA-induced phosphorylation of NF-κB and the CsA-induced expression of vimentin and α-smooth muscle actin, suggesting the attenuation of inflammation and fibrosis. In conclusion, the activation of HIF by cobalt may ameliorate the CsA-induced nephropathy by inhibiting apoptosis, inflammation, and fibrosis. © 2012 Tohoku University Medical Press.
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Collections - 2. Clinical Science > Department of Nephrology and Hypertension > 1. Journal Articles
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