Effects of specific interleukin-1beta-converting enzyme inhibitor on ischemic acute renal failure in murine models.
OBJECTIVE
To study the effect of selective interleukin-1beta-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-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.


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-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).


CONCLUSIONS
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.
Liu
Hua-feng
HF
Institute of Nephrology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China. hf-liu@263.net
Liang
Dong
D
Wang
Li-ming
LM
Zhou
Nan
N
Yao
Cui-wei
CW
Hong
Tao
T
Tang
De-shen
DS
Chen
Xiao-wen
XW
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D001806:Blood Urea Nitrogen; D020170:Caspase 1 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D020382:Interleukin-18 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D051379:Mice; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015843:Serpins / Q000494:pharmacology*; D014764:Viral Proteins / Q000494:pharmacology*
D000590:Amino Acid Chloromethyl Ketones; D020382:Interleukin-18; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D020011:Protective Agents; D012333:RNA, Messenger; D015843:Serpins; D014764:Viral Proteins; D007371:Interferon-gamma; C074641:interleukin-1beta-converting enzyme inhibitor; D003404:Creatinine; D020170:Caspase 1