Geranylgeranylacetone ameliorates ischemic acute renal failure via induction of Hsp70
Geranylgeranylacetone ameliorates ischemic acute renal failure via induction of Hsp70
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DOI：
10.1111/j.1523-1755.2005.00326.x
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发表时间：
2005-06-01
影响因子：
19.6
通讯作者：
Matsuo, S
中科院分区：
文献类型：
--
作者：
Suzuki, S;Maruyama, S;Matsuo, S
背景。热休克蛋白（HSPs）是众所周知的细胞保护蛋白。香叶基香叶基丙酮（GGA），一种抗溃疡剂，最近被证明可以诱导Hsp70。本研究旨在探讨gga的肾保护作用。GGA对主要热休克蛋白（Hsp90）的诱导作用。Hsp70。采用Western blot方法研究Hsc70、Hsp60和Hsp32)在大鼠肾或大鼠肾小管上皮细胞（R-TECs）原代培养中的表达。免疫组化法检测Hsp70的定位。采用大鼠缺血再灌注（I/R）损伤模型，研究GGA对肾脏的保护作用。在诱导I/R损伤前24小时和1小时分别给予GGA （400 mg/kg）、GGA加槲皮素预处理（100 mg/kg）或载药。再灌注后24小时处死大鼠。进行组织学分析和末端脱氧核苷酸转移酶（TdT）介导的脱氧尿苷三磷酸（dUTP）镍端标记（TUNEL）试验。测定血尿素氮（BUN）和血清肌酐。采用GGA （10 μ mol/L）或载药处理R-TECs，然后在氧化应激条件下（0.5 mmol/L过氧化氢）或缺血条件下（2 nmol/L NaCN和20 mmol/L 2-脱氧葡萄糖，无培养基葡萄糖）培养，研究GGA对细胞的保护作用。口服GGA诱导Hsp70在肾脏中的表达（在24小时达到峰值），但不诱导Hsp90、Hsc70、Hsp60或Hsp32。槲皮素可阻断Hsp70的诱导。免疫组化显示Hsp70主要定位于小管上皮细胞。GGA预处理大鼠可显著降低I/R损伤后BUN和血清肌酐水平。组织学检查显示GGA明显减轻了小管损伤和巨噬细胞浸润。GGA组tunel阳性细胞数量也明显减少。槲皮素。Hsp70诱导抑制剂。消除了GGA对肾脏的保护作用在体外研究中，gga在r - tec中诱导Hsp70，在2 ~ 4小时达到峰值。氧化应激和缺血刺激均可诱导r - tec细胞凋亡。GGA在两种情况下均能显著抑制凋亡细胞的数量。结果支持GGA诱导Hsp70的假设。保护小管上皮细胞免于凋亡。从而改善I/R损伤引起的肾小管损伤。目前的研究表明，GGA将是治疗急性肾功能衰竭或预防移植肾损害的有效工具。
Background. Heat shock proteins (HSPs) are well known as cytoprotective proteins. Geranylgeranyl acetone (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 I 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 cytoprotcctive properties of GGA were also studied in vitro by treating R-TECs with GGA (10 mu mol/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.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.