Geranylgeranylacetone ameliorates ischemic acute renal failure via induction of Hsp70
2005
Geranylgeranylacetone ameliorates ischemic acute renal failure via induction of
Hsp70. Background Heat shock proteins (HSPs) are well known as
cytoprotectiveproteins. 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
Hsp70was 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)
assaywere performed. Blood urea nitrogen (BUN) and serum creatinine was also measured. The
cytoprotectiveproperties of GGA were also studied in vitro by treating R-
TECswith GGA (10 μmol/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-
deoxyglucosein the absence of medium glucose). Results Oral administration of GGA induced
Hsp70expression in the kidney (which peaked at 24 hours) but did not induce
Hsp90, Hsc70,
Hsp60, or Hsp32. The induction of
Hsp70was blocked by quercetin. Immunohistochemistry showed that
Hsp70was 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
Hsp70induction, eliminated these renoprotective effects of GGA. In in vitro study, GGA-induced
Hsp70in 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. Conclusion 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.
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