Geranylgeranylacetone ameliorates ischemic acute renal failure via induction of Hsp70.
BACKGROUND
Heat shock proteins (HSPs) are well known as cytoprotective proteins. Geranylgeranylacetone (GGA), an antiulcer agent, has recently been shown to induce Hsp70. This study was performed to investigate the renoprotective properties of GGA.


METHODS
The effect of GGA on the induction of the major HSPs (Hsp90, Hsp70, Hsc70, Hsp60, and Hsp32) was studied in the rat kidney or rat primary cultures of tubular epithelial cells (R-TECs) by Western blot. Localization of Hsp70 was determined by immunohistochemistry. The renoprotective effects of GGA were studied using a rat model of ischemia/reperfusion (I/R) injury. GGA (400 mg/kg), GGA with quercetin pretreatment (100 mg/kg), or a vehicle was given to rats 24 hours and again 1 hour prior to the induction of I/R injury. Rats were sacrificed at 24 hours after reperfusion. Histologic analyses and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) assay were performed. Blood urea nitrogen (BUN) and serum creatinine was also measured. The cytoprotective properties of GGA were also studied in vitro by treating R-TECs with GGA (10 mumol/L) or a vehicle, followed by incubation in culture medium with oxidative stress condition (0.5 mmol/L hydrogen peroxide) or ischemic condition (2 nmol/L NaCN and 20 mmol/L 2-deoxyglucose in the absence of medium glucose).


RESULTS
Oral administration of GGA induced Hsp70 expression in the kidney (which peaked at 24 hours) but did not induce Hsp90, Hsc70, Hsp60, or Hsp32. The induction of Hsp70 was blocked by quercetin. Immunohistochemistry showed that Hsp70 was localized mainly in the tubular epithelial cells. Preconditioning rats with GGA significantly decreased BUN and serum creatinine levels after I/R injury. Histologic examination revealed that GGA significantly attenuated tubular damage and macrophage infiltration. The number of TUNEL-positive cells also decreased significantly in the GGA group. Quercetin, an inhibitor of Hsp70 induction, eliminated these renoprotective effects of GGA. In in vitro study, GGA-induced Hsp70 in R-TECs, which peaked at 2 to 4 hours. Both oxidative stress and ischemic stimuli induced apoptosis in R-TECs. GGA significantly suppressed the number of apoptotic cells in both conditions.


CONCLUSIONS
The results support the hypothesis that GGA induces Hsp70, protects tubular epithelial cells from apoptosis, and thus ameliorates tubular damage by I/R injury. The present study suggests that GGA would be a useful tool in treating acute renal failure or preventing transplanted kidney damage in the clinical setting.
Suzuki
Satoshi
S
Division of Clinical Immunology, Department of Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Maruyama
Shoichi
S
Sato
Waichi
W
Morita
Yoshiki
Y
Sato
Fumihiko
F
Miki
Yusuke
Y
Kato
Sawako
S
Katsuno
Masahisa
M
Sobue
Gen
G
Yuzawa
Yukio
Y
Matsuo
Seiichi
S
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D011794:Quercetin; D006861:Hydrogen Peroxide; C031049:geranylgeranylacetone