Role of caspases in human renal proximal tubular epithelial cell apoptosis.
In the present study, we have used an in vitro model of apoptosis using primary human renal proximal tubular epithelial (RPTE) cells to investigate the mechanisms involved in renal cell apoptosis. Treatment of RPTE cells with okadaic acid for 24-48 h induced apoptosis in a concentration-dependent manner. Apoptosis was accompanied by the activation of the p38 mitogen-activated protein kinase (MAPK) pathway followed by the activation of caspase-9, -3, and -7. The induction of caspase activity correlated with the proteolytic cleavage of beta-catenin, suggesting that beta-catenin is a caspase substrate. The caspase inhibitor, Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), resulted in a dose-dependent inhibition of apoptosis and beta-catenin cleavage. These data suggest that okadaic acid-induced apoptosis is p38 MAPK and caspase-dependent and that proteolytic cleavage of beta-catenin by caspases is likely to be a downstream molecular event associated with the morphological and cytoskeletal changes induced during apoptosis.
Wong
V Y
VY
Department of Renal Pharmacology, GlaxoSmithKline, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939, USA.
Keller
P M
PM
Nuttall
M E
ME
Kikly
K
K
DeWolf
W E
WE
Lee
D
D
Ali
S M
SM
Nadeau
D P
DP
Grygielko
E T
ET
Laping
N J
NJ
Brooks
D P
DP
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D015534:Trans-Activators; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases
D000590:Amino Acid Chloromethyl Ketones; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D009842:Oligopeptides; D015534:Trans-Activators; C427308:benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D051176:beta Catenin; D019319:Okadaic Acid; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases