Probenecid induces the recovery of renal ischemia/reperfusion injury via the blockade of Pannexin 1/P2X7 receptor axis

Theodor Bilharz Research Institute

Bibliographic Information

Authors: El-Maadawy W.H.; Hassan M.; Badawy M.H.; AbuSeada A.; Hafiz E.

Journal: Life Sciences

Publisher: Elsevier Inc.

Publication Date: November 2022

Volume / Issue: Volume 308

Article No.: 120933

ISSN: 243205

DOI: 10.1016/j.lfs.2022.120933

Scopus: View on Scopus

PubMed: 36075473

Document Type: Article

Authors and Affiliations

El-Maadawy W.H., Pharmacology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Hassan M., Immunology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Badawy M.H., Urology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; AbuSeada A., Anesthesia Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Hafiz E., Electron Microscopy Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt

Abstract

Renal ischemia/reperfusion injury (RI/RI) is one of the main driving causes of acute kidney injury. However, effective treatment to limit injury and promote recovery and/or survival is still unavailable. Probenecid (PBN), a drug indicated for refractory gout, exhibits protective activities against several preclinical diseases including cerebral and myocardial I/RI via Pannexin 1 (Panx1) and P2X7 receptors' (P2X7R) inhibition. However, its protective role against RI/RI has not been previously addressed. Accordingly, we subjected rats to bilateral RI/RI with/or without PBN treatment. Twenty-four hours post-reperfusion, PBN showed mild tubular injury and reduced serum nephrotoxicity indices, gene and protein expression levels of Panx 1 and P2X7R, and ATP and pro-inflammatory cytokines' levels. The nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome signaling was also downregulated, as demonstrated by reduced gene and protein expression of NLRP3 and caspase-1, along with suppressed IL-1β maturation. Furthermore, PBN enhanced Tregs activity as indicated by elevated FoxP3 gene expression, IL-10, and TGF-β renal levels. On day 5 post-reperfusion, PBN noticeably enhanced renal recovery, as demonstrated by intact tubular epithelium and restored nephrotoxicity indices, Panx 1 and P2X7R gene and protein expression levels, ATP and pro-inflammatory cytokine levels, and NLRP3 inflammasome signaling. Besides, renal Tregs activity was also significantly increased. Our study elaborates for the first time the effectiveness of PBN in recovering post-ischemic renal injury through synergistic inhibition in Panx1/P2X7R axis leading to inactivation of NLRP3 inflammasome signaling and activation of Tregs in ischemic renal tissues. Therefore, PBN can be considered a promising drug for RI/RI treatment. © 2022 Elsevier Inc.

Keywords

NLRP3 inflammasome; P2X7 receptors; Pannexin 1 channels; Probenecid; Renal ischemia/reperfusion injury; Tregs; Adenosine Triphosphate; Animals; Caspase 1; Cytokines; Forkhead Transcription Factors; Inflammasomes; Interleukin-10; Ischemia; Kidney; NLR Family, Pyrin Domain-Containing 3 Protein; Nucleotides; Rats; Receptors, Purinergic P2X7; Reperfusion Injury; Transforming Growth Factor beta; interleukin 10; membrane protein; pannexin 1; purinergic P2X7 receptor; transcription factor FOXP3; unclassified drug; cryopyrin; cytokine; forkhead transcription factor; inflammasome; interleukin 1beta converting enzyme; nucleotide; animal experiment; animal model; animal tissue; Article; controlled study; down regulation; gene expression level; male; nephrotoxicity; nonhuman; protein expression level; rat; renal ischemia reperfusion injury; single drug dose; animal; metabolism

Citation Information

Scopus Citations: 17

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