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Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity
Xiujin Shen1,2,3,4,5, Haibing Wang6, Chunhua Weng7,8,9,10,11
1Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. xiujinshen@zju.edu.cn.
Abstract:
Chemotherapy drug-induced nephrotoxicity limits clinical applications for treating cancers. Pyroptosis, a newly discovered programmed cell death, was recently reported to be associated with kidney diseases. However, the role of pyroptosis in chemotherapeutic drug-induced nephrotoxicity has not been fully clarified. Herein, we demonstrate that the chemotherapeutic drug cisplatin or doxorubicin, induces the cleavage of gasdermin E (GSDME) in cultured human renal tubular epithelial cells, in a time- and concentration-dependent manner. Morphologically, cisplatin- or doxorubicin-treated renal tubular epithelial cells exhibit large bubbles emerging from the cell membrane. Furthermore, activation of caspase 3, not caspase 9, is associated with GSDME cleavage in cisplatin- or doxorubicin-treated renal tubular epithelial cells. Meanwhile, silencing GSDME alleviates cisplatin- or doxorubicin-induced HK-2 cell pyroptosis by increasing cell viability and decreasing LDH release. In addition, treatment with Ac-DMLD-CMK, a polypeptide targeting mouse caspase 3-Gsdme signaling, inhibits caspase 3 and Gsdme activation, alleviates the deterioration of kidney function, attenuates renal tubular epithelial cell injury, and reduces inflammatory cytokine secretion in vivo. Specifically, GSDME cleavage depends on ERK and JNK signaling. NAC, a reactive oxygen species (ROS) inhibitor, reduces GSDME cleavage through JNK signaling in human renal tubular epithelial cells. Thus, we speculate that renal tubular epithelial cell pyroptosis induced by chemotherapy drugs is mediated by ROS-JNK-caspase 3-GSDME signaling, implying that therapies targeting GSDME may prove efficacious in overcoming chemotherapeutic drug-induced nephrotoxicity.
Insights
Chemotherapy drugs like cisplatin cause kidney damage by triggering pyroptosis, a cell death process involving gasdermin E (GSDME). Targeting GSDME may prevent this chemotherapy-induced nephrotoxicity.
Area of Science:
- Biomedical Science
- Molecular Biology
- Toxicology
Background:
- Chemotherapy-induced nephrotoxicity is a major clinical challenge.
- Pyroptosis, a programmed cell death pathway, is implicated in kidney diseases.
- The specific role of pyroptosis in chemotherapy-induced kidney damage remains unclear.
Purpose of the Study:
- To investigate the role of pyroptosis, specifically gasdermin E (GSDME) cleavage, in chemotherapy-induced nephrotoxicity.
- To elucidate the signaling pathways involved in GSDME-mediated pyroptosis induced by chemotherapeutic agents.
- To explore potential therapeutic strategies targeting GSDME to mitigate kidney injury.
Main Methods:
- Utilized cultured human renal tubular epithelial cells (HK-2 cells) and in vivo mouse models.
- Administered chemotherapeutic drugs (cisplatin, doxorubicin) and measured GSDME cleavage, caspase activation, and cell viability.
- Employed gene silencing techniques (siGSDME) and pharmacological inhibitors (Ac-DMLD-CMK, NAC) to investigate signaling pathways (ROS, JNK, ERK, caspase 3).
Main Results:
- Cisplatin and doxorubicin induced time- and concentration-dependent GSDME cleavage in renal tubular cells.
- GSDME cleavage was associated with caspase 3 activation and pyroptotic morphological changes.
- Silencing GSDME or inhibiting caspase 3-GSDME signaling reduced cell death and improved kidney function in vivo.
- GSDME cleavage was dependent on ERK and JNK signaling, with reactive oxygen species (ROS) influencing this pathway via JNK.
Conclusions:
- Chemotherapy-induced nephrotoxicity involves pyroptosis mediated by the ROS-JNK-caspase 3-GSDME signaling axis in renal tubular epithelial cells.
- GSDME plays a critical role in chemotherapy-induced kidney injury.
- Targeting GSDME presents a promising therapeutic avenue for preventing or treating chemotherapy-induced nephrotoxicity.
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