Erythropoietin Protects Against Exertional Rhabdomyolysis-induced Acute Kidney Injury in Association with Preferential M2 Macrophage Polarization and Hemeoxygenase-1 Activation

¹ Department of Medical Physiology, Faculty of Medicine, Benha University, Benha, Qalubyia, Egypt

² Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Benha University, Qalubyia, Egypt

³ Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Sharkia, Egypt

^*Corresponding Author

Marwa Hassan Muhammad.

Department of Medical Physiology

Faculty of Medicine

Benha University

Qalubyia

Egypt

www.fmed.bu.edu.eg

Tel: 00201009655692

E-Mail: drmarwa.hassan@yahoo.com

Abstract

Background: Exertional rhabdomyolysis (ER)-induced acute kidney injury (AKI) is a serious health threat associated with strenuous physical exercise. Erythropoietin (EPO) is a pleiotropic hormone with its immunomodulator function still unclear. We investigated the renoprotective effect of EPO in EXR-induced AKI, with an emphasis on macrophages phenotypic polarization and associated hemeoxygenase1 (HO1) bioactivity.

Methods: Strenuous exercise was applied to rats, either or not preceded by EPO alone or combined with the HO1 enzyme blocker, Zinc protoporphyrins (Zn-PP). Serum levels of creatine phosphokinase, myoglobin, urea nitrogen, creatinine, and carboxyhemoglobin (COHb) % were estimated. In addition, we examined the inflammatory cytokines IL10 and TNFα, macrophages phenotypic markers, HO1 expression, and renal pathology.

Results: EPO pre-treatment resulted in significant decreases in blood urea nitrogen, serum creatinine and myoglobin, tubular injury score, and intratubular cast % in addition to TNF-α decrease, IL10 increase with a preferential switching of macrophage polarization to the reparative M2 phenotype as anti-inflammatory effect. Furthermore, EPO pre-treatment was associated with an increase in HO1 protein expression and COHb%. Such effects were significantly reversed when HO1 activity blocker, Zn-PP, was co-administered.

Conclusion: Our findings highlight the value of EPO as a prophylactic therapeutic agent against EXR-induced AKI. Additionally, they suggest an underpinning role for HO1 in the EPO-induced modulation of macrophage polarization towards the M2 phenotype.

Keywords:Erythropoietin, M2 macrophage, Heamoxygenase-1, Exertional rhabdomyolysis-induced acute kidney injury

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