ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-OR12

Proximal Tubule Pannexin 1 Channel Regulates Cell Death and Inflammation During AKI

Session Information

  • AKI Research: Mechanisms
    November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
    Abstract Time: 04:39 PM - 04:48 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

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

Pannexin 1 (Panx1) serves as a conduit for release of small metabolites during cellular stress and injury. Pharmacological inhibition or genetic deletion of Panx1 in mice is protective against renal ischemia-reperfusion injury (IRI). We hypothesized that proximal tubule Panx1 mediated metabolite release exacerbates AKI by inducing proximal tubule cell death and by increasing inflammatory cell recruitment to the injured kidney.

Methods

We performed bilateral IRI or cisplatin-induced AKI (cis-AKI) in a transgenic mouse that overexpresses the human isoform of PANX1 globally (PANX1Tg), specifically in proximal tubules (PTECPTg), or endothelium (ECPTg) and evaluated extent of kidney injury. PANX1 overexpressing proximal tubule epithelial cells (OX) were treated with cisplatin in vitro to assess cell death and mitochondrial damage. Flow cytometry was performed to measure leukocyte infiltration in the kidneys after cis-AKI.

Results

PANX1Tg mice had significant rise in plasma creatinine and expression of kidney injury marker, Ngal, in the kidneys in both models of AKI compared to their littermate controls. PTECPTg mice also had significantly higher injury compared to their littermates in both cis-AKI or IRI-AKI. In vitro studies showed that OX cells had higher cisplatin-induced cell death than wildtype (WT) cells. Furthermore, in a co-culture model in which both WT and OX cells were cultured together, OX cells had higher cisplatin-induced cell death. Conditioned media from cisplatin treated OX cells induced higher cell death compared to conditioned media from cisplatin treated WT cells. The higher cisplatin-induced cell death was associated with reduced mitochondrial function and increased mitochondrial ROS production. Assessment of mitochondria in kidneys showed a significant reduction in Drp1 levels in PANX1Tg kidneys compared to WT controls. Cisplatin induced a higher infiltration of neutrophils, CD8-positive T cells, and CD11b-positive dendritic cells in the kidneys of PTECPTg animals compared to WT.

Conclusion

We showed that PANX1 overexpression resulted in overt renal injury during AKI that is in part mediated by reduced mitochondrial function, increased cell death, and inflammation. Selective strategies to inhibit Panx1 could help prevent or treat AKI.

Funding

  • NIDDK Support