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 language | English |
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Pages (from-to) | F397-405 |
Number of pages | 9 |
Journal | American Journal of Physiology - Renal Physiology |
Volume | 295 |
Issue number | 2 |
DOIs | |
Publication status | Published - 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