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Inhibition of pannexin-1 channel activity by adiponectin in podocytes: Role of acid ceramidase activation.

Authors
  • Li, Guangbi1
  • Zhang, Qinghua1
  • Hong, Jinni1
  • Ritter, Joseph K1
  • Li, Pin-Lan2
  • 1 Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, United States of America. , (United States)
  • 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, United States of America. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Biochimica et biophysica acta. Molecular and cell biology of lipids
Publication Date
Oct 01, 2018
Volume
1863
Issue
10
Pages
1246–1256
Identifiers
DOI: 10.1016/j.bbalip.2018.07.016
PMID: 30077007
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The pannexin-1 (Panx1) channel has been reported to mediate the release of ATP that is involved in local tissue inflammation, obesity, and many chronic degenerative diseases. It remains unknown whether Panx1 is present in podocytes and whether this channel in podocytes mediates ATP release leading to glomerular inflammation or fibrosis. To answer these questions, we first characterized the expression of Panx channels in podocytes. Among the three known pannexins, Panx1 was the most enriched in podocytes, either cultured or native in mouse glomeruli. Using a Port-a-Patch planar patch-clamp system, we recorded a large voltage-gated outward current through podocyte membrane under the Cs+in/Na+out gradient. Substitution of gluconate or aspartate for chloride in the bath solution blocked voltage-gated outward currents and shifted the reversal potential of Panx1 currents to the right, indicating the anion permeability of this channel. Pharmacologically, the recorded voltage-gated outward currents were substantially attenuated by specific Panx1 channel inhibitors. Given the anti-inflammatory and intracellular ATP restorative effects of adiponectin, we tested whether this adipokine inhibits Panx1 channel activity to block ATP release. Adiponectin blocked Panx1 channel activity in podocytes. Mechanistically, inhibition of acid ceramidase (AC) remarkably enhanced Panx1 channel activity under control conditions and prevented the inhibition of Panx1 channel by adiponectin. Correspondingly, intracellular addition of AC products, sphingosine or sphingosine-1-phosphate (S1P), blocked Panx1 channel activity, while elevation of intracellular ceramide had no effect on Panx1 channel activity. These results suggest that adiponectin inhibits Panx1 channel activity in podocytes through activation of AC and associated elevation of intracellular S1P. Published by Elsevier B.V.

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