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Kidney Week

Abstract: PO0444

Prohibitin Ligand FL3 Protects Renal Proximal Tubular Cells Against ATP-Depletion-Induced Injury

Session Information

  • AKI: Novel Insights
    November 04, 2021 | Location: On-Demand, Virtual Only
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Zhou, Xun, Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
  • Dong, Zheng, Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
Background

FL3 is a synthesized ligand of prohibitins, a family of proteins located on and important for mitochondrial inner membrane. FL3 has been reported to protect neurons and cardiomyocytes by regulating mitochondrial function. Whether FL3 can protect kidney cells against cell stress remains unknown. This study aims to evaluate the effect of FL3 on ATP-depletion-induced cell death in renal proximal tubular cells (RPTCs).

Methods

RPTCs were pre-treated with 50nM FL3 for 3 hours and incubated with 10mM azide in glucose-free Krebs-Ringer bicarbonate solution for 3 hours to induce ATP depletion. The cells were then returned to a normal cultured medium for recovery. Cells were also exposed to the same concentration of FL3 throughout the ATP depletion and recovery phases. Mitochondrial changes including mitochondrial fragmentation, Bax translocation, cytochrome C release, prohibitin complex breakdown, OPA1 and OMA1 proteolysis were examined immediately after azide treatment; whereas apoptosis events including apoptotic morphology and caspase activation were examined after 2 hours of recovery.

Results

RPTCs with azide-induced ATP depletion developed apoptotic morphology, caspase 3 activation and PARP cleavage, which were suppressed by FL3. Mitochondrial fragmentation and membrane leakage of cytochrome C were increased in RPTCs during ATP depletion. FL3 suppressed mitochondrial fragmentation and inhibited mitochondrial injury. Under cell stress, the large prohibitin ring complex was disrupted to medium and small complexes, releasing OMA1 to cleave the inner membrane fusion protein OPA1. FL3 treatment decreased both the small prohibitin complex and the activation of OMA1. FL3 also partially prevented the degradation of the long isoforms of OPA1 during ATP depletion.

Conclusion

FL3 can protect against ATP-depletion-induced injury in renal tubular cells, likely through the regulation of mitochondrial dynamics.

Funding

  • NIDDK Support