Dual Therapy with Esculin and Erythropoietin Attenuates Renal Ischemia-Reperfusion Injury via P2x7 Receptor and Nlrp3 Inflammasome Inhibition, and Pi3k/akt Activation

E. Hafiz¹, W. H. El-Maadawy², M. Hassan³, M. H. Badawy⁴, S. Eldahshan⁴, A. AbuSeada⁵

¹Clinical Research Laboratory Department, Theodor Bilharz Research Institute, Giza, Egypt, ²Pharmacology Department, Theodor Bilharz Research Institute, Giza, Egypt, ³Immunology Department, Theodor Bilharz Research Institute, Giza, Egypt, ⁴Urology Department, Theodor Bilharz Research Institute, Giza, Egypt, ⁵Anesthesia Department, Theodor Bilharz Research Institute, Giza, Egypt

Meeting: 2022 American Transplant Congress

Abstract number: 673

Keywords: Apoptosis, Inflammation, Renal function, Renal injury

Topic: Basic Science » Basic Science » 14 - Ischemia Reperfusion

Session Information

Session Name: Ischemia Reperfusion

Session Type: Poster Abstract

Date: Saturday, June 4, 2022

Session Time: 5:30pm-7:00pm

Presentation Time: 5:30pm-7:00pm

Location: Hynes Halls C & D

*Purpose: Renal ischemia/reperfusion (RI/R) is an inevitable condition during renal transplantation with critical clinical outcomes. Accordingly, effective therapies are crucially required.

*Methods: In this study, the therapeutic effects of esculin (ESC, coumarin compound with reported P2X7 receptor inhibitor activity) alone and in combination with erythropoietin (EPO, hematopoietic protein with renoprotective properties) were investigated against RI/R injury in rats and possible underlying mechanisms were delineated. ESC (50 mg/kg) and EPO (1000 IU/kg) were administered for 7 days and 30 min prior to RI, respectively; 24 h following reperfusion, blood, and kidney samples were harvested and processed for subsequent biochemical, RT-PCR, histopathological examinations, transmission electron microscopy, and immunohistochemical (IHC) studies.

*Results: Results revealed that pretreatment with either ESC or EPO reduced serum nephrotoxicity indices (creatinine, urea, and NGAL), renal oxidative stress (indicated by elevated GPx and SOD, and reduced MDA levels), inflammatory (IL-1β, TNF-α, and NF-κB p65), and apoptosis (indicated by mitigated Bax levels and caspase-3 immunohistochemical expression and enhanced bcl-2 levels) markers. They also ameliorated the renal histopathological injury on endothelial and tubular epithelial levels. Notably, ESC showed markedly inhibited P2X7 receptors and NLRP3 inflammasome signaling (indicated by modulated 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.

*Conclusions: 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, and activating PI3K/Akt pathway.

To cite this abstract in AMA style:

Hafiz E, El-Maadawy WH, Hassan M, Badawy MH, Eldahshan S, AbuSeada A. Dual Therapy with Esculin and Erythropoietin Attenuates Renal Ischemia-Reperfusion Injury via P2x7 Receptor and Nlrp3 Inflammasome Inhibition, and Pi3k/akt Activation [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/dual-therapy-with-esculin-and-erythropoietin-attenuates-renal-ischemia-reperfusion-injury-via-p2x7-receptor-and-nlrp3-inflammasome-inhibition-and-pi3k-akt-activation/. Accessed November 21, 2024.

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