TEAD1 Regulates Cisplatin-Induced AKI
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Tran, Melanie, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Jiao, Baihai, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Du, Hao, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Song, Bo, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Wang, Yanlin, University of Connecticut School of Medicine, Farmington, Connecticut, United States
Cisplatin is an inorganic platinum-based chemotherapeutic agent that is widely used for the treatment of solid tumors. However, a known complication of cisplatin administration is acute kidney injury (AKI). Despite recent advances in examining the molecular mechanisms, no potential strategy exists to prevent kidney injury. In this study, we examined the role of TEA domain family member 1 (TEAD1) in the pathogenesis of cisplatin-induced AKI.
We generated proximal tubule-specific TEAD1 knockout (TEAD1PKO) mice by crossing TEAD1 floxed mice with PEPCK-Cre mice. Ten-week-old male TEAD1PKO mice and TEAD1f/f (TEAD1CON) mice were administered a single intraperitoneal dose of cisplatin (20mg/kg body weight), or vehicle (saline) to induce AKI. Blood and kidneys were collected at 72h for assessment of kidney function, tubular cell injury, cell death and inflammation. Lentivirus transfection was utilized to knock down the expression of TEAD1 in mouse tubular epithelial cells in vitro. Cells were treated with cisplatin (20μM, 24h) for determination of intracellular ROS and mitochondrial function.
TEAD1 expression was upregulated in tubular epithelial cells of kidneys with cisplatin-induced AKI. TEAD1PKO mice treated with cisplatin had increased tubular cell damage and enhanced kidney dysfunction compared with TEAD1CON mice. Additionally, TEAD1PKO mice had augmented necroptotic cell death and inflammatory response compared with TEAD1CON mice treated with cisplatin. Knockdown of TEAD1 in mouse tubular epithelial cells promoted intracellular ROS levels, which was associated with reduced ATP production and impaired oxygen consumption rate.
Taken together, our results indicate that TEAD1 plays an important role in the pathogenesis of cisplatin–induced AKI through regulation of necroptosis and inflammation which may be associated with impaired mitochondrial function. TEAD1 may represent a novel therapeutic target for cisplatin-induced AKI.
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