Co-treatment with Esculin and erythropoietin protects against renal ischemia–reperfusion injury via P2X7 receptor inhibition and PI3K/Akt activation

Theodor Bilharz Research Institute

Bibliographic Information

Authors: El-Maadawy W.H.; Hassan M.; Hafiz E.; Badawy M.H.; Eldahshan S.; AbuSeada A.R.; El-Shazly M.A.M.; Ghareeb M.A.

Journal: Scientific Reports

Publisher: Nature Research

Publication Date: 14 April 2022

Volume / Issue: Volume 12 / Issue 1

Article No.: 6239

ISSN: 20452322

DOI: 10.1038/s41598-022-09970-8

Scopus: View on Scopus

PubMed: 35422072

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

El-Maadawy W.H., Pharmacology Department, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt; Hassan M., Immunology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt; Hafiz E., Electron Microscopy Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt; Badawy M.H., Urology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt; Eldahshan S., Urology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt; AbuSeada A.R., Anesthesia Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt; El-Shazly M.A.M., Medicinal Chemistry Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt; Ghareeb M.A., Medicinal Chemistry Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt

Abstract

Renal ischemia/reperfusion (RI/R) is a critical clinical outcome with slightly reported improvement in mortality and morbidity. Effective therapies are still crucially required. Accordingly, the therapeutic effects of esculin (ESC, LCESI-MS/MS-isolated compound from Vachellia farnesiana flowers extract, with reported P2X7 receptor inhibitor activity) alone and in combination with erythropoietin (EPO) were investigated against RI/R injury and the possible underlying mechanisms were delineated. ESC and EPO were administered for 7 days and 30 min prior to RI, respectively. Twenty-four hour following reperfusion, blood and kidney samples were collected. Results revealed that pretreatment with either ESC or EPO reduced serum nephrotoxicity indices, renal oxidative stress, inflammatory, and apoptosis markers. They also ameliorated the renal histopathological injury on both endothelial and tubular epithelial levels. Notably, ESC markedly inhibited P2X7 receptors and NLRP3 inflammasome signaling (downregulated NLRP3 and Caspase-1 gene expressions), whereas EPO significantly upregulated PI3K and Akt gene expressions, also p-PI3K and p-Akt levels in renal tissues. ESC, for the first time, demonstrated effective protection against RI/R-injury and its combination with EPO exerted maximal renoprotection when compared to each monotherapy, thereby representing an effective therapeutic approach via inhibiting oxidative stress, inflammation, renal tubular and endothelial injury, apoptosis, and P2X7 receptors expression, and activating PI3K/Akt pathway. © 2022, The Author(s).

Keywords

Apoptosis; Erythropoietin; Esculin; Humans; Kidney; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Purinergic P2X7; Reperfusion Injury; Tandem Mass Spectrometry; cryopyrin; phosphatidylinositol 3 kinase; protein kinase B; purinergic P2X7 receptor; genetics; human; metabolism

Citation Information

Scopus Citations: 17

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