Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney.
In this report we investigate the molecular mechanisms that contribute to tissue damage following ischemia and ischemia coupled with reperfusion (ischemia/reperfusion) in the rat heart and kidney. We observe the activation of three stress-inducible mitogen-activated protein (MAP) kinases in these tissues: p38 MAP kinase and the 46- and 55-kDa isoforms of Jun N-terminal kinase (JNK46 and JNK55). The heart and kidney show distinct time courses in the activation of p38 MAP kinase during ischemia but no activation of either JNK46 or JNK55. These two tissues also respond differently to ischemia/reperfusion. In the heart we observe activation of JNK55 and p38 MAP kinase, whereas in the kidney all three kinases are active. We also examined the expression pattern of two stress-responsive genes, c-Jun and ATF3. Our results indicate that in the heart both genes are induced by ischemia and ischemia/reperfusion. However, in the kidney c-Jun and ATF3 expression is induced only by ischemia/reperfusion. To correlate these molecular events with tissue damage we examined DNA laddering, a common marker of apoptosis. A significant increase in DNA laddering was evident in both heart and kidney following ischemia/reperfusion and correlated with the pattern of kinase activation, supporting a link between stress kinase activation and apoptotic cell death in these tissues.
Yin
T
T
Novartis Pharmaceuticals Corp., Summit, New Jersey 07901, USA.
Sandhu
G
G
Wolfgang
C D
CD
Burrier
A
A
Webb
R L
RL
Rigel
D F
DF
Hai
T
T
Whelan
J
J
D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation; D007511:Ischemia / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000098:blood supply*; D007674:Kidney Diseases / Q000201:enzymology*; D048670:MAP Kinase Kinase 4; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017202:Myocardial Ischemia / Q000201:enzymology*; D015425:Myocardial Reperfusion; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D011494:Protein Kinases; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases