Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury

Ewen M Harrison, Eva Sharpe, Christopher O Bellamy, Stephen J McNally, Luke Devey, O James Garden, James A Ross, Stephen J Wigmore

Research output: Contribution to journalArticlepeer-review

Abstract

Heat shock proteins (Hsps) are protective in models of transplantation, yet practical strategies to upregulate them remain elusive. The heat shock protein 90-binding agent (HBA) geldanamycin and its analogs (17-AAG and 17-DMAG) are known to upregulate Hsps and confer cellular protection but have not been investigated in a model relevant to transplantation. We examined the ability of HBAs to upregulate Hsp expression and confer protection in renal adenocarcinoma (ACHN) cells in vitro and in a mouse model of kidney ischemia-reperfusion (I/R) injury. Hsp70 gene expression was increased 30-40 times in ACHN cells treated with HBAs, and trimerization and DNA binding of heat shock transcription factor-1 (HSF1) were demonstrated. A three- and twofold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHN cells treated with HBAs. HBAs protected ACHN cells from an H2O2-mediated oxidative stress, and HSF1 short interfering RNA was found to abrogate HBA-mediated Hsp induction and protection. In vivo, Hsp70 was upregulated in the kidneys, liver, lungs, and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from I/R injury. Therefore, HBAs mediate upregulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury.
Original languageEnglish
Pages (from-to)F397-405
Number of pages9
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number2
DOIs
Publication statusPublished - Aug 2008

Keywords

  • Adenocarcinoma
  • Animals
  • Benzoquinones
  • Cell Line, Tumor
  • Disease Models, Animal
  • Enzyme Inhibitors
  • HSP27 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Humans
  • Kidney
  • Kidney Neoplasms
  • Lactams, Macrocyclic
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Proteins
  • Oxidative Stress
  • RNA, Small Interfering
  • Reperfusion Injury

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