Liu Hua-feng, Liang Dong, Wang Li-ming, Zhou Nan, Yao Cui-wei, Hong Tao, Tang De-shen, Chen Xiao-wen
Institute of Nephrology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China.
Acta Pharmacol Sin. 2005 Nov;26(11):1345-51. doi: 10.1111/j.1745-7254.2005.00200.x.
To study the effect of selective interleukin-1beta-converting enzyme (ICE, caspase-1) inhibitor on ischemic acute renal failure (ARF).
Mouse models of ischemic ARF were treated with the specific ICE inhibitor AC-YVAD-CMK. A renal function assay and renal morphological studies were employed to estimate the renal protective effect of AC-YVAD-CMK. The survival rate of mouse models was also analyzed by a time series test. Furthermore, renal ICE activity, mature interleukin-18 (IL-18) protein expression and interferon-gamma (IFN-gamma) mRNA expression were also detected by fluorescent enzyme-linked immunosorbent assay (ELISA), ELISA, and semi-quantitative reverse transcription-polymerase chain reaction, respectively.
The levels of blood urea nitrogen (BUN) and serum creatinine (Scr) increased remarkably in the model controls compared with the sham-operated groups (P<0.01). Typical renal tubular necrosis was found in the model controls. Renal ICE activity, mature IL-18 protein expression, and IFN-gamma mRNA expression were also increased significantly in the model controls compared with the sham-operated groups. The levels of BUN and Scr in the AC-YVAD-CMK therapy group were decreased significantly compared with the untreated model controls (P<0.01). Renal tubulointerstitial lesion was also attenuated significantly (P<0.05). AC-YVAD-CMK therapy alleviated the clinical features of ARF, and increased the survival rate (P<0.01). Furthermore, AC-YVAD-CMK therapy also decreased ICE activity, mature IL-18 protein expression, and IFN-gamma mRNA expression in renal tissue (P<0.05).
The selective ICE inhibitor AC-YVAD-CMK can effectively protect the kidney from acute ischemic lesions. This protective effect is associated with decreased renal ICE activity and suppressed IL-18 maturation and IFN-gamma mRNA transcription.
研究选择性白细胞介素-1β转换酶（ICE，半胱天冬酶-1）抑制剂对缺血性急性肾衰竭（ARF）的影响。
用特异性ICE抑制剂AC-YVAD-CMK治疗缺血性ARF小鼠模型。采用肾功能测定和肾脏形态学研究来评估AC-YVAD-CMK的肾脏保护作用。还通过时间序列试验分析小鼠模型的存活率。此外，分别用荧光酶联免疫吸附测定（ELISA）、ELISA和半定量逆转录-聚合酶链反应检测肾脏ICE活性、成熟白细胞介素-18（IL-18）蛋白表达和干扰素-γ（IFN-γ）mRNA表达。
与假手术组相比，模型对照组的血尿素氮（BUN）和血清肌酐（Scr）水平显著升高（P<0.01）。在模型对照组中发现典型的肾小管坏死。与假手术组相比，模型对照组的肾脏ICE活性、成熟IL-18蛋白表达和IFN-γmRNA表达也显著增加。与未治疗的模型对照组相比，AC-YVAD-CMK治疗组的BUN和Scr水平显著降低（P<0.01）。肾小管间质病变也显著减轻（P<0.05）。AC-YVAD-CMK治疗减轻了ARF的临床特征，并提高了存活率（P<0.01）。此外，AC-YVAD-CMK治疗还降低了肾组织中的ICE活性、成熟IL-18蛋白表达和IFN-γmRNA表达（P<0.05）。
选择性ICE抑制剂AC-YVAD-CMK可有效保护肾脏免受急性缺血性损伤。这种保护作用与肾脏ICE活性降低、IL-18成熟受抑制和IFN-γmRNA转录受抑制有关。
