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Abstract: FR-OR04

Proximal Tubule Pannexin 1 Channel Regulates Mitochondrial Function and Cell Death During AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Poudel, Nabin, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Skrypnyk, Nataliya, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Zheng, Shuqiu, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Medina, Christopher B., University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Goggins, Eibhlin, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Rosin, Diane L., University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Ravichandran, Kodi S., University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Okusa, Mark D., University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background

Pannexin 1 (Panx1) channel serves as a conduit for release of small metabolites upon activation during cellular stress and injury. We have previously shown that pharmacological inhibition or genetic deletion of Panx1 in mice prior to injury is protective against renal ischemia-reperfusion injury (IRI). How Panx1 contributes to acute kidney injury (AKI) is unknown. We hypothesized that Panx1 induces cell death by mediating both intracellular and extracellular events.

Methods

We performed IRI or cisplatin-induced AKI in a novel human Panx1 overexpressing mouse (hPANX1-Tg) and in proximal tubule specific Panx1 overexpressing mice (hPANX1-TgPTEC) and assessed plasma creatinine, renal expression of neutrophil gelatin associated lipocalin (Ngal), and acute tubular necrosis scoring. We challenged PANX1 overexpressing murine proximal tubule-derived TKPTS cells with cisplatin and assessed cell death and mitochondrial changes. We next assessed the changes in mitochondria of kidneys from cisplatin challenged hPANX1-Tg animals.

Results

hPANX1-Tg mice had significant rise in plasma creatinine and expression of Ngal in the kidneys in both models of AKI compared to their littermate controls. Proximal tubule specific overexpression of hPANX1 also resulted in overt injury following IRI or cisplatin-induced AKI compared to littermate controls. In vitro studies showed that overexpression of PANX1 in TKPTS cells resulted in significantly higher cell death compared to controls during cisplatin challenge, which was associated with reduced mitochondrial biogenesis, mitochondrial function, increased mitochondrial ROS production, and altered mitochondrial quality control. Assessment of mitochondria in kidneys showed a significant reduction in Drp1 levels in kidneys from hPANX1-Tg animals compared to littermate controls after cisplatin challenge.

Conclusion

PANX1 overexpression results in overt renal injury during AKI that is in part mediated by reduced mitochondrial function and quality control in proximal tubules that facilitates proximal tubule cell death. These results provide strong rationale for the development of selective strategies to inhibit Panx1 in the prevention or treatment of AKI.

Funding

  • NIDDK Support