Role of caspases in human renal proximal tubular epithelial cell apoptosis

• Published in: European journal of pharmacology 2001-12, Vol.433 (2), p.135-140
• Main Authors: Wong, Victoria Y, Keller, Paul M, Nuttall, Mark E, Kikly, Kristine, DeWolf, Walter E, Lee, Dennis, Ali, Shujath M, Nadeau, Daniel P, Grygielko, Eugene T, Laping, Nicholas J, Brooks, David P
• Format: Article
• Language: English
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Apoptosis; beta Catenin; Biological and medical sciences; Caspase; Caspases - physiology; Cytoskeletal Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Kidney Tubules, Proximal - cytology; Mitogen-Activated Protein Kinases - physiology; Okadaic acid; Okadaic Acid - pharmacology; Oligopeptides - pharmacology; p38; p38 Mitogen-Activated Protein Kinases; Polycystic kidney disease; Trans-Activators; Vertebrates: urinary system; β-Catenin
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)01517-5

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 β-catenin, suggesting that β-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 β-catenin cleavage. These data suggest that okadaic acid-induced apoptosis is p38 MAPK and caspase-dependent and that proteolytic cleavage of β-catenin by caspases is likely to be a downstream molecular event associated with the morphological and cytoskeletal changes induced during apoptosis.