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Thromboxane A2 mediates cisplatin-induced apoptosis of renal tubule cells
S Jariyawat1, M Takeda, M Kobayashi
1Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Abstract:
The purpose of this study was to elucidate the role of thromboxane A2 (TXA2) in cisplatin-induced apoptosis of mouse renal cells derived from the terminal proximal tubule (S3). RT-PCR analysis revealed that S3 cells express TXA2 receptor mRNA. A TXA2 receptor antagonist, KW-3635, dose-dependently inhibited cisplatin-induced apoptosis of S3 cells. Treatment of S3 cells with a TXA2 agonist, STA2, induced a significant decrease in their viability and resulted in the characteristic ladder pattern resulting from intranucleosomal DNA cleavage. Treatment with KW-3635 resulted in attenuation of the increase in c-fos mRNA expression level in cisplatin-treated S3 cells. In conclusion, TXA2 appears to mediate cisplatin-induced apoptosis of S3 cells by inducing an increase in the level of c-fos mRNA expression.
Insights
Thromboxane A2 (TXA2) plays a key role in cisplatin-induced kidney cell death. Blocking the TXA2 receptor with KW-3635 protected mouse renal cells from this damage, suggesting a new therapeutic target.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Cisplatin is a widely used chemotherapy agent with known nephrotoxic side effects.
- The precise mechanisms underlying cisplatin-induced kidney cell apoptosis are not fully understood.
- Thromboxane A2 (TXA2) is a bioactive lipid implicated in various cellular processes.
Purpose of the Study:
- To investigate the role of Thromboxane A2 (TXA2) in cisplatin-induced apoptosis of mouse renal S3 cells.
- To determine if TXA2 receptor antagonists can mitigate cisplatin nephrotoxicity.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) to detect TXA2 receptor mRNA expression in S3 cells.
- Treatment of S3 cells with cisplatin, a TXA2 receptor antagonist (KW-3635), and a TXA2 agonist (STA2).
- Assessment of apoptosis using DNA fragmentation assays and measurement of c-fos mRNA expression.
Main Results:
- S3 cells were found to express TXA2 receptor mRNA.
- KW-3635 significantly and dose-dependently inhibited cisplatin-induced apoptosis in S3 cells.
- STA2 treatment decreased cell viability and induced DNA fragmentation, mimicking cisplatin effects.
- KW-3635 attenuated the cisplatin-induced increase in c-fos mRNA expression.
Conclusions:
- TXA2 mediates cisplatin-induced apoptosis in mouse renal S3 cells.
- This mediation appears to occur through the upregulation of c-fos mRNA expression.
- Targeting the TXA2 pathway may offer a protective strategy against cisplatin nephrotoxicity.