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DAP5 ameliorates cisplatin-induced apoptosis of renal tubular cells
Jian-jun Gao1, Guang-yan Cai, Yi-chun Ning
1Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, PR China.
Background:
Nephrotoxicity of cisplatin limits its clinical application. Cisplatin-induced acute renal tubular epithelial cell apoptosis is one of the major mechanisms of cisplatin nephrotoxicity. Here, the role and regulation of death-associated protein 5 (DAP5) in cisplatin-induced tubular cell apoptosis were investigated.
Methods:
After upregulation of DAP5 expression by plasmid transfection and downregulation of DAP5 expression by small interfering RNA in human kidney tubular epithelial cell line (HKC) cells, the degree of cell apoptosis was assessed by flow cytometric analysis. The expression of Bax and Bcl-2 proteins was detected by Western blot analysis. The relationship between the PI3K/Akt/mTOR signaling pathway and DAP5 was also evaluated.
Results:
During cisplatin-induced apoptosis in HKC cells, DAP5 underwent proteolytic fragmentation, yielding an 86-kDa species, DAP5/p86. Overexpression of DAP5/p97 and DAP5/p86 increased the translation of Bcl-2 and reduced the extent of cisplatin-induced apoptosis. Knockdown of DAP5 expression using small interfering RNA decreased the translation of Bcl-2 and increased the degree of apoptosis. Neither manipulation affected the expression of Bax. DAP5 expression was positively regulated by the PI3K/Akt/mTOR signaling pathway.
Conclusion:
Collectively, the results from the present study revealed a new role for DAP5 in cisplatin-induced apoptosis: DAP5/p97 and DAP5/p86 enhanced the translation of the anti-apoptotic protein Bcl-2 and inhibited cisplatin-induced apoptosis. The PI3K/Akt/mTOR signaling pathway may positively regulate the expression of DAP5.
Insights
Death-associated protein 5 (DAP5) plays a protective role in cisplatin nephrotoxicity by enhancing Bcl-2 translation and reducing kidney cell apoptosis. The PI3K/Akt/mTOR pathway regulates DAP5 expression.
Area of Science:
- Nephrology
- Molecular Biology
- Cellular Biology
Background:
- Cisplatin nephrotoxicity is a major clinical limitation.
- Cisplatin-induced apoptosis in renal tubular cells contributes significantly to kidney damage.
- The role of death-associated protein 5 (DAP5) in this process was unclear.
Purpose of the Study:
- To investigate the function of DAP5 in cisplatin-induced kidney tubular cell apoptosis.
- To explore the regulatory mechanisms of DAP5 in this context.
Main Methods:
- Manipulated DAP5 expression (overexpression and knockdown) in human kidney tubular epithelial cells (HKC).
- Assessed apoptosis using flow cytometry.
- Analyzed Bax and Bcl-2 protein expression via Western blot.
- Evaluated the link between the PI3K/Akt/mTOR pathway and DAP5.
Main Results:
- Cisplatin induced DAP5 fragmentation into DAP5/p86.
- Overexpression of DAP5 (full-length and p86) increased Bcl-2 translation and reduced apoptosis.
- DAP5 knockdown decreased Bcl-2 translation and enhanced apoptosis.
- Bax expression remained unaffected.
- The PI3K/Akt/mTOR pathway positively regulated DAP5 expression.
Conclusions:
- DAP5, particularly its fragments DAP5/p97 and DAP5/p86, inhibits cisplatin-induced apoptosis by promoting Bcl-2 translation.
- The PI3K/Akt/mTOR signaling pathway is involved in the positive regulation of DAP5 expression.
