Human adipose tissue derived mesenchymal stem cells aggravate chronic cyclosporin nephrotoxicity by the induction of oxidative stress

PLoS One. 2013;8(3):e59693. doi: 10.1371/journal.pone.0059693. Epub 2013 Mar 26.

Abstract

The aim of this study was to investigate whether hATMSCs protect against cyclosporine (CsA)-induced renal injury. CsA (7.5 mg/kg) and hATMSCs (3×10(6)/5 mL) were administered alone and together to rats for 4 weeks. The effect of hATMSCs on CsA-induced renal injury was evaluated by assessing renal function, interstitial fibrosis, infiltration of inflammatory cells, and apoptotic cell death. Four weeks of CsA-treatment produced typical chronic CsA-nephropathy. Combined treatment with CsA and hATMSCs did not prevent these effects and showed a trend toward further renal deterioration. To evaluate why hATMSCs aggravated CsA-induced renal injury, we measured oxidative stress, a major mechanism of CsA-induced renal injury. Both urine and serum 8-hydroxydeoxyguanosine(8-OHdG) levels were higher in the CsA+hATMSCs group than in the CsA group (P<0.05). An in vitro study showed similar results. Although the rate of apoptosis did not differ significantly between HK-2 cells cultured in hATMSCs-conditioned medium and those cultured in DMEM, addition of CsA resulted in greater apoptosis in HK-2 cells cultured in hATMSCs-conditioned medium. Addition of CsA increased oxidative stress in the hATMSCs-conditioned medium. The results of our study suggest that treatment with hATMSCs may aggravate CsA-induced renal injury because hATMSCs cause oxidative stress in the presence of CsA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Adipose Tissue / cytology*
  • Animals
  • Apoptosis / drug effects
  • Cell Line
  • Culture Media, Conditioned
  • Cyclosporine / adverse effects*
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / blood
  • Deoxyguanosine / urine
  • Fibrosis
  • Humans
  • Kidney / drug effects*
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney / physiopathology
  • Male
  • Mesenchymal Stem Cell Transplantation / adverse effects*
  • Mesenchymal Stem Cells / cytology*
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors

Substances

  • Culture Media, Conditioned
  • Cyclosporine
  • 8-Hydroxy-2'-Deoxyguanosine
  • Deoxyguanosine

Grant support

This study was supported by a grant (A092258) from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.