Apoptosis and chemokine induction after renal ischemia-reperfusion.
BACKGROUND
One of the earliest prerequisites for the development of inflammation after ischemia-reperfusion (I/R) is local chemokine expression. We recently demonstrated that apoptosis, characterized by intracellular caspase-activation, contributes to the development of inflammation after I/R.


METHODS
The contribution of apoptosis was investigated using the pan-caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2F in a murine model of renal I/R. Renal expression of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC was studied using RT-PCR and immunohistology. Measuring myeloperoxidase activity and serum ureum and creatinine levels assessed neutrophil influx and kidney dysfunction.


RESULTS
We demonstrate renal up-regulation of KC and MIP-2 after 1 to 16 hr of reperfusion. Treatment with the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2F effectively prevented I/R-induced renal apoptosis, KC, and MIP-2 up-regulation after 2 hr of reperfusion as well as neutrophil influx and functional impairment after 24 hr of reperfusion.


CONCLUSIONS
These data for the first time show that chemokine induction following I/R is dependent on caspase activation.
Daemen
M A
MA
Department of General Surgery of the University of Maastricht, The Netherlands.
de Vries
B
B
van't Veer
C
C
Wolfs
T G
TG
Buurman
W A
WA
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D012079:Renal Circulation; D015424:Reperfusion; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D000590:Amino Acid Chloromethyl Ketones; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C426824:benzyloxycarbonyl-valyl-alanyl-(methyl)aspartic acid fluoromethyl ketone; D020169:Caspases