Abstract: FR-PO128
PKM2 Exacerbates Cisplatin-Induced AKI Through Regulation of STAT3
Session Information
- AKI: Mechanisms - II
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Wen, Lu, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Dong, Zheng, Augusta University, Augusta, Georgia, United States
Background
Pyruvate kinase M2 (PKM2) is an important rate-limiting enzyme catalyzing the last step of glycolysis. However, in addition to its vital role in energy metabolism in cytoplasm, PKM2 can translocate into the nucleus and interacts with signal transducer and activator of transcription 3 (STAT3) to regulate cell differentiation and inflammation. The role of nuclear PKM2 in renal pathophysiology is unknown.
Methods
To investigate the role of PKM2 in cisplatin-induced AKI, we generated kidney proximal tubule-specific PKM2 knock-out mice (PT-PKM2-KO) by crossing PKM2-floxed mice with PEPCK-CRE mice. PT-PKM2-KO or wild type mice of 8-10 weeks were intraperitoneally injected with 25 mg/kg of cisplatin to induce acute kidney injury (AKI). In vitro, we transfected PKM2-overexpressing plasmids into rat renal proximal tubular cells (RPTCs), followed by treatment with 20μM cisplatin for 24h. To determine the involvement of STAT3, we tested Stattic (inhibitor of STAT3) in PKM2 knock-out and wild type mice.
Results
Deficiency of proximal tubule PKM2 mitigated cisplatin-induced AKI in mice, suggesting a injurious role of PKM2. Consistently, overexpression of PKM2 aggravated cisplatin-induced apoptosis in RPTCs. Moreover, both STAT3 and phosphorylated STAT3 were increased in mice renal cortex cisplatin-induced AKI in mice. Notably, Stattic ameliorated cisplatin-induced AKI in wild type mice. but not in PKM2 knock-out mice.
Conclusion
These results indicate that PKM2/STAT3 signaling contributes to renal tubular injury in cisplatin-induced AKI, suggesting the PKM2/STAT3 pathway as a new therapeutic target in cisplatin nephrotoxicity.
Funding
- NIDDK Support