Activation of hypoxia-inducible factor by cobalt is associated with the attenuation of tissue injury and apoptosis in cyclosporine-induced nephropathy

Se Won Oh, Jeong Myung Ahn, Yun Mi Lee, Sejoong Kim, Ho Jun Chin, Dong Wan Chae, Ki Young Na

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)197-206
Number of pages10
JournalTohoku Journal of Experimental Medicine
Volume226
Issue number3
DOIs
Publication statusPublished - 2012 Feb 27
Externally publishedYes

Fingerprint

Cobalt
Cyclosporine
Chemical activation
Tissue
Apoptosis
Wounds and Injuries
Kidney
Hypoxia-Inducible Factor 1
Caspase 3
Fibrosis
Cells
Hypoxia
Transplantation (surgical)
Inflammation
Sodium-Restricted Diet
Phosphorylation
Macrophages
Organ Transplantation
Vimentin
Nutrition

Keywords

  • Apoptosis
  • Cyclosporine
  • Fibrosis
  • Hypoxia-inducible factor 1
  • Inflammation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Activation of hypoxia-inducible factor by cobalt is associated with the attenuation of tissue injury and apoptosis in cyclosporine-induced nephropathy. / Oh, Se Won; Ahn, Jeong Myung; Lee, Yun Mi; Kim, Sejoong; Chin, Ho Jun; Chae, Dong Wan; Na, Ki Young.

In: Tohoku Journal of Experimental Medicine, Vol. 226, No. 3, 27.02.2012, p. 197-206.

Research output: Contribution to journalArticle

Oh, Se Won ; Ahn, Jeong Myung ; Lee, Yun Mi ; Kim, Sejoong ; Chin, Ho Jun ; Chae, Dong Wan ; Na, Ki Young. / Activation of hypoxia-inducible factor by cobalt is associated with the attenuation of tissue injury and apoptosis in cyclosporine-induced nephropathy. In: Tohoku Journal of Experimental Medicine. 2012 ; Vol. 226, No. 3. pp. 197-206.
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AU - Kim, Sejoong

AU - Chin, Ho Jun

AU - Chae, Dong Wan

AU - Na, Ki Young

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