Abstract: SA-PO121
Slc25a21 in Cisplatin-Induced AKI: A New Target for Renal Tubular Epithelial Protection by Regulating Mitochondrial Metabolic Homeostasis
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Chen, Huimei, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore
- Zhang, Aihua, Nanjing Medical University, Nanjing, China
- Su, Xin, Nanjing Medical University, Nanjing, China
Background
Acute kidney injury (AKI) is a global health issue frequently induced by cisplatin therapy. Dysfunctional mitochondria in tubular epithelial cells are key drivers of kidney injury, and the regulation of mitochondrial metabolites is proposed to be beneficial in kidney protection. Here, we highlighted that maintaining a mitochondrial 2-oxodicarboxylate carrier, Slc25a21 in cisplatin-induced AKI protected against tubular apoptosis and inflammation by restoring mitochondrial metabolic homeostasis.
Methods
Kidney samples from AKI patients and cisplatin-induced mice models were to evaluate the association of renal Slc25a21 expression and AKI progression. Slc25a21 expression was upregulated using AAV9 system via in situ injection and plasmid transfection in kidney proximal tubular epithelial cells. AKI severity was evaluated through histological assessments and kidney function tests. Cellular apoptosis and inflammatory response were assessed using TUNEL assays, flow cytometry, and ELISA for cytokines (e.g., IL-18 and TNFα). Additionally, mitochondrial function and metabolic alterations were examined through Seahorse assays and metabolomics analysis.
Results
It was observed that renal Slc25a21 is highly expressed in proximal tubular epithelial cells and showed a negative correlation with kidney function in both AKI patients and cisplatin-induced murine models. Maintaining renal Slc25a21 expression alleviated cisplatin-induced tubular injury by reducing cellular apoptosis and inflammatory responses. It also helped restore respiratory ATP production, mitochondrial biogenesis, and integrity in acutely injured tubular epithelial cells. Mechanistically, reduced Slc25a21 levels in AKI disrupted mitochondrial 2-oxoadipate transport, altering the influx of related metabolites, and particularly affecting the tricarboxylic acid cycle, while restoration of Slc25a21 reversed these effects in mitochondrial metabolic homeostasis.
Conclusion
Our findings suggest that suppression Slc25a21 contributes to AKI and sustaining Slc25a21 expression could prevent the progress of AKI via fuel metabolite transport and the restoration of mitochondrial homeostasis in tubular epithelial cells. We believe our findings will contribute to the advancement of mechanistic insights and potential therapeutic strategies to treat AKI.
Funding
- Government Support – Non-U.S.