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Am J Physiol Regul Integr Comp Physiol 278: R763-R769, 2000;
0363-6119/00 $5.00
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Vol. 278, Issue 3, R763-R769, March 2000

Apoptosis in polycystic kidney disease: involvement of caspases

Shujath M. Ali1, Victoria Y. Wong1, Kristine Kikly2, Todd A. Fredrickson1, Paul M. Keller3, Walter E. DeWolf Jr.3, Dennis Lee4, and David P. Brooks1

1 Departments of Renal Pharmacology, 2 Molecular Biology, 3 Molecular Recognition, and 4 Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406

Polycystic kidney disease (PKD) is characterized by the development of large renal cysts and progressive loss of renal function. Although the cause of the development of renal cysts is unknown, recent evidence suggests that excessive apoptosis occurs in PKD. With the use of terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, we have confirmed the presence of apoptotic bodies in cystic kidneys of congenital polycystic kidney (cpk) disease mice carrying a homozygous mutation at 3 wk of age. Apoptosis was localized primarily to the interstitium with little evidence of cell death in cyst epithelium or noncystic tubules. In addition, we observed that the expression of various caspases, bax and bcl-2, was upregulated in cystic kidneys. With the use of various substrates in enzyme activity assays, we have demonstrated a greater than sevenfold increase in caspase 4 activity and a sixfold increase in caspase 3 activity. These data suggest that there is a caspase-dependent apoptosis pathway associated with PKD and support the hypothesis that apoptotic cell death contributes to cyst formation in PKD.

cpk mice; cysteine proteases


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