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Apoptosis in polycystic kidney disease: involvement of caspases
1Departments of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Abstract:
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.
Insights
Polycystic kidney disease (PKD) involves cyst formation and kidney function loss. This study shows increased apoptosis, particularly caspase activity, in PKD kidneys, suggesting it contributes to cyst development.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Biology
Background:
- Polycystic kidney disease (PKD) is a genetic disorder characterized by renal cyst development and progressive loss of kidney function.
- The precise mechanisms driving cyst formation in PKD remain largely unknown, but emerging evidence points to excessive apoptosis.
- Apoptosis, or programmed cell death, is increasingly implicated in the pathogenesis of various kidney diseases.
Purpose of the Study:
- To investigate the presence and localization of apoptosis in the context of polycystic kidney disease.
- To examine the expression and activity of key apoptotic regulators, including caspases, bax, and bcl-2, in PKD kidneys.
- To determine if a caspase-dependent apoptotic pathway is associated with cystogenesis in PKD.
Main Methods:
- Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining was employed to detect apoptotic bodies in cystic kidneys of congenital polycystic kidney (cpk) disease mice.
- Immunohistochemical analysis was performed to assess the expression of apoptosis-related proteins (caspases, bax, bcl-2).
- Enzyme activity assays using specific substrates were conducted to quantify the activity of caspases 3 and 4.
Main Results:
- Apoptotic bodies were confirmed in the cystic kidneys of cpk mice, primarily localized to the interstitium.
- There was minimal evidence of apoptosis within the cyst epithelium or non-cystic tubules.
- Upregulation of caspases, bax, and bcl-2 expression was observed in cystic kidneys, alongside a significant increase in caspase 4 (sevenfold) and caspase 3 (sixfold) activity.
Conclusions:
- The findings strongly suggest a caspase-dependent apoptosis pathway is active in polycystic kidney disease.
- Apoptotic cell death, particularly in the renal interstitium, is implicated as a contributing factor to cyst formation and progression in PKD.
- These results provide a mechanistic link between apoptosis and the pathogenesis of polycystic kidney disease.