Acta Pharmacologica Sinica 2005 November; 26 (11): 1345-1351; doi: 10.1111/j.1745-7254.2005.00200.x

 
Original Article
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Effects of specific interleukin-1β-converting enzyme inhibitor on ischemic acute renal failure in murine models1
 

Hua-feng LIU2, Dong LIANG, Li-ming WANG, Nan ZHOU, Cui-wei YAO, Tao HONG, De-shen TANG, Xiao-wen CHEN

Institute of Nephrology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China

 

Aim: To study the effect of selective interleukin-1β-converting enzyme (ICE, caspase-1) inhibitor on ischemic acute renal failure (ARF).

Methods: 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-g (IFN-g) mRNA expression were also detected by fluorescent enzyme-linked immunosorbent assay (ELISA), ELISA, and semi-quantitative reverse transcription-polymerase chain reaction, respectively.

Results: 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-γ 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-γ mRNA expression in renal tissue (P<0.05).


Conclusion:
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-γ mRNA transcription.

 

Keywords: kidney failure; ischemia; caspase-1; inter-leukin-1β-converting enzyme inhibitor; interleukin-1; interleukin-18; interferon type II

 

1 Project supported by the Fatal Diseases Prevention and Cure Program of Zhanjiang (2003).
2 Correspondence to Prof Hua-feng LIU.
Phn 86-759-238-7164.
E-mail hf-liu@263.net
Received 2005-05-19     Accepted 2005-07-01

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