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Updated: May 6, 2026
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Targeting STEAP4 ameliorates pericytes loss and vascular dysfunction in cisplatin induced mouse acute kidney injury
Chuanfeng Xiong1, Jieying Qi2, Xiaohu Chen3
1Department of Nephrology and Rheumatology, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan, 528200, China.
Abstract:
Nephrotoxicity is the most common complication of cisplatin, and effective therapeutic strategies are still limited. Vascular dysfunction is thought to be early response after cisplatin administration and contributes to renal damage. However, the precise mechanisms underlying this process have yet to be fully elucidated. In this study, we observed a significant increase in renal vascular permeability following cisplatin administration in vivo, accompanied by a rapid loss of perivascular pericytes. Consistently, in vitro experiments revealed that cisplatin markedly accelerated cell death in primary human kidney microvascular pericytes (HKMPs). RNA-sequencing and proteomics analysis further identified a significant downregulation of six-transmembrane epithelial antigen of the prostate 4 (STEAP4) mRNA and protein expression in HKMPs after cisplatin exposure. Mechanistically, reduced STEAP4 expression facilitates iron accumulation and lipid peroxidation in HKMPs, leading to potentiated ferroptosis, whereas STEAP4 overexpression conferred protection against cisplatin-induced pericytes injury. Finally, targeted delivery of AAV9-STEAP4 via renal artery injection efficiently increased renal STEAP4 expression, reduced pericyte loss, and attenuated renal vascular leakage. Furthermore, the AAV9-STEAP4 group exhibited significantly decreased kidney injury compared to the AAV9-NC group. Collectively, these findings demonstrate that STEAP4 mediates pericyte injury in renal vascular dysfunction and suggest that targeting STEAP4 could represent a novel therapeutic strategy for cisplatin-induced acute kidney injury (AKI).
Insights
Cisplatin causes kidney damage by harming pericytes, a process linked to reduced STEAP4. Restoring STEAP4 levels protects against this injury, offering a potential therapy for cisplatin-induced acute kidney injury.
Area of Science:
- Nephrology
- Molecular Biology
- Vascular Biology
Background:
- Cisplatin is a common chemotherapy drug with significant nephrotoxicity.
- Vascular dysfunction and pericyte injury are early events in cisplatin-induced kidney damage.
- The exact molecular mechanisms driving these early events remain unclear.
Purpose of the Study:
- To investigate the role of six-transmembrane epithelial antigen of the prostate 4 (STEAP4) in cisplatin-induced kidney pericyte injury and vascular dysfunction.
- To explore STEAP4 as a potential therapeutic target for mitigating cisplatin nephrotoxicity.
Main Methods:
- In vivo and in vitro models using cisplatin exposure on human kidney microvascular pericytes (HKMPs).
- RNA-sequencing and proteomics to analyze gene and protein expression changes.
- Investigated the role of STEAP4 in ferroptosis and oxidative stress.
- Utilized adeno-associated virus serotype 9 (AAV9) for targeted delivery of STEAP4 to the kidney.
Main Results:
- Cisplatin induced significant pericyte loss and increased renal vascular permeability.
- STEAP4 expression was markedly downregulated in HKMPs following cisplatin exposure.
- Reduced STEAP4 expression promoted iron accumulation, lipid peroxidation, and ferroptosis in pericytes.
- Overexpression of STEAP4 protected pericytes from cisplatin-induced injury.
- AAV9-mediated delivery of STEAP4 attenuated pericyte loss, reduced vascular leakage, and decreased kidney injury.
Conclusions:
- STEAP4 plays a critical role in mediating pericyte injury and vascular dysfunction during cisplatin exposure.
- Targeting STEAP4 offers a promising novel therapeutic strategy for preventing or treating cisplatin-induced acute kidney injury (AKI).
