JNK/SAPK and p38 SAPK-2 mediate mechanical stretch-induced apoptosis via caspase-3 and -9 in NRK-52E renal epithelial cells.
OBJECTIVE
In renal epithelial cells, mechanical forces produced from urinary obstruction serve as potential mediators of apoptosis by activating specific intracellular signaling pathways. In this study, we sought to further define the role of JNK and p38 SAPK-2 pathway and caspase activation in stretch-induced apoptosis.


METHODS
Immortalized cell lines derived from the various components of the nephron were subjected to cyclical stretch and their differential apoptotic response was assessed. Pharmacologic inhibitors and Western blot analysis were used to assess the involvement of the MAPK pathways. Caspases' activity was assessed with ELISA and by Western blot analysis.


RESULTS
Stretch-induced apoptosis was dependent upon the cell phenotype and the degree of stretch. In NRK-52E cells, it was mediated through both JNK and p38 SAPK-2 pathways, and inhibition of either pathway reduced the degree of stretch-induced apoptosis. Stretched cells showed increased activity of caspase-3 and -9 but not -2 or -8. Stretch-induced apoptosis was modulated by inhibition of caspase-3 and to a lesser extent by caspase-9.


CONCLUSIONS
These findings suggest that stretch induces apoptosis in renal epithelial cells through the specific activation of JNK/SAPK and p38 SAPK-2 pathways and is dependent on the activation of caspase-3 and -9.
Nguyen
Hiep T
HT
Department of Urology, University of California, San Francisco, California, USA. hiep.nguyen@childrens.harvard.edu
Hsieh
Michael H
MH
Gaborro
Anna
A
Tinloy
Bradford
B
Phillips
Courtney
C
Adam
Rosalyn M
RM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D051379:Mice; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases