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Updated: Aug 21, 2026
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells
Lucia Cilenti1, George A Kyriazis, Mangala M Soundarapandian
1Biomolecular Science Center, Burnett College of Biomedical Science, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826, USA.
Abstract:
Omi/HtrA2 is a mitochondrial proapoptotic serine protease that is able to induce both caspase-dependent and caspase-independent cell death. After apoptotic stimuli, Omi is released to the cytoplasm where it binds and cleaves inhibitor of apoptosis proteins. In this report, we investigated the role of Omi in renal cell death following cisplatin treatment. Using primary mouse proximal tubule cells, as well as established renal cell lines, we show that the level of Omi protein is upregulated after treatment with cisplatin. This upregulation is followed by the release of Omi from mitochondria to the cytoplasm and degradation of XIAP. Reducing the endogenous level of Omi protein using RNA interference renders renal cells resistant to cisplatin-induced cell death. Furthermore, we show that the proteolytic activity of Omi is necessary and essential for cisplatin-induced cell death in this system. When renal cells are treated with Omi's specific inhibitor, ucf-101, they become significantly resistant to cisplatin-induced cell death. Ucf-101 was also able to minimize cisplatin-induced nephrotoxic injury in animals. Our results demonstrate that Omi is a major mediator of cisplatin-induced cell death in renal cells and suggest a way to limit renal injury by specifically inhibiting its proteolytic activity.
Insights
The mitochondrial protease Omi/HtrA2 mediates cisplatin-induced kidney cell death by degrading inhibitor of apoptosis proteins. Inhibiting Omi/HtrA2 protects renal cells and minimizes cisplatin nephrotoxicity.
Area of Science:
- Mitochondrial biology
- Cell death pathways
- Renal toxicology
Background:
- Omi/HtrA2 is a mitochondrial serine protease involved in apoptosis.
- It induces cell death through caspase-dependent and -independent mechanisms.
- Omi/HtrA2 cleaves inhibitor of apoptosis proteins (IAPs) after apoptotic stimuli.
Purpose of the Study:
- To investigate the role of Omi/HtrA2 in cisplatin-induced renal cell death.
- To determine if Omi/HtrA2 is a key mediator of this process.
- To explore the therapeutic potential of inhibiting Omi/HtrA2 activity.
Main Methods:
- Upregulation and subcellular localization of Omi/HtrA2 in renal cells treated with cisplatin.
- Assessment of XIAP degradation following cisplatin exposure.
- RNA interference to reduce Omi/HtrA2 levels in renal cells.
- Treatment with Omi/HtrA2 inhibitor ucf-101 in vitro and in vivo.
- Evaluation of renal cell viability and cisplatin-induced nephrotoxicity.
Main Results:
- Cisplatin treatment upregulated Omi/HtrA2 protein levels in renal cells.
- Omi/HtrA2 was released from mitochondria to the cytoplasm, leading to XIAP degradation.
- Reducing Omi/HtrA2 levels via RNA interference conferred resistance to cisplatin-induced cell death.
- Omi/HtrA2's proteolytic activity was essential for cisplatin-induced renal cell death.
- Ucf-101 treatment significantly protected renal cells from cisplatin and minimized nephrotoxic injury in vivo.
Conclusions:
- Omi/HtrA2 is a critical mediator of cisplatin-induced renal cell death.
- Inhibition of Omi/HtrA2's proteolytic activity represents a promising strategy to mitigate cisplatin nephrotoxicity.
- Targeting Omi/HtrA2 could offer a novel therapeutic approach for preventing kidney damage during chemotherapy.
