Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury.
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.
Tissue Injury and Repair Group, University of Edinburgh, Edinburgh, UK. mail@ewenharrison.com
Ewen M
EM
Harrison
Eva
E
Sharpe
Christopher O
CO
Bellamy
Stephen J
SJ
McNally
Luke
L
Devey
O James
OJ
Garden
James A
JA
Ross
Stephen J
SJ
Wigmore
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin; C001277:geldanamycin