Apoptosis and chemokine induction after renal ischemia-reperfusion

Transplantation. 2001 Apr 15;71(7):1007-11. doi: 10.1097/00007890-200104150-00032.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis* / drug effects
  • Caspases / metabolism
  • Chemokine CXCL1
  • Chemokine CXCL2
  • Chemokines / genetics
  • Chemokines / metabolism*
  • Chemokines, CXC*
  • Chemotactic Factors / genetics
  • Chemotactic Factors / metabolism
  • Enzyme Activation / physiology
  • Growth Substances / genetics
  • Growth Substances / metabolism
  • Intercellular Signaling Peptides and Proteins*
  • Ischemia / metabolism
  • Ischemia / physiopathology*
  • Kidney / drug effects
  • Kidney / metabolism
  • Mice
  • RNA, Messenger / metabolism
  • Renal Circulation*
  • Reperfusion
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / physiopathology*
  • Time Factors
  • Up-Regulation / drug effects

Substances

  • Amino Acid Chloromethyl Ketones
  • Chemokine CXCL1
  • Chemokine CXCL2
  • Chemokines
  • Chemokines, CXC
  • Chemotactic Factors
  • Cxcl1 protein, mouse
  • Cxcl2 protein, mouse
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • benzyloxycarbonyl-valyl-alanyl-(methyl)aspartic acid fluoromethyl ketone
  • Caspases