EPOR/CD131-mediated attenuation of rotenone-induced retinal degeneration is associated with upregulation of autophagy genes

Soldatov VO1, Pokrovskiy MV1, Puchenkova OA1, Zhunusov NS1, Krayushkina AM1, Grechina AV2, Soldatova MO3, Lapin KN4, Bushueva OYu3
About authors

1 Belgorod State National Research University, Belgorod, Russia

2 Sechenov First Moscow State Medical University, Moscow, Russia

3 Kursk State Medical University, Kursk, Russia

4 Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russia

Correspondence should be addressed: Vladislav O. Soldatov
Pobedy, 85, Belgorod, 308015, Russia; moc.liamg@votadlosmrahp

About paper

Funding: State Assignment "Laboratory for Genome Editing in Biomedicine and Veterinary FZWG-2021-0016".

Author contribution: Soldatov VO — concept and design of the study, writing of the manuscript; Pokrovsky MV, Lapin KN — consulting on the concept and design of the study; Puchenkova OA — collection of samples for histological examination and target gene expression analysis; Puchenkova OA, Zhunusov NS — modeling of the rotenone-induced retinal degeneration; Zhunusov NS, Krayushkina AM — in vitro assay of rotenone cytoprotective activity; Grechina AV — morphological study; Bushueva OYu, Soldatova MO — RNA extraction, quantitative PCR assay.

Compliance with ethical standards: the study was approved by the ethical committee of the Belgorod State National Research University (Protocol № 06-07/21 of 15 July 2021); all procedures were performed in accordance with the Regulations on Laboratory Practice in the Russian Federation of 2003, in compliance with the 86/609 EEC Directive and ARRIVE guidelines.

Received: 2022-07-11 Accepted: 2022-08-01 Published online: 2022-08-12

Mitochondrial dysfunction is a key driver of neurodegeneration. This study aimed to evaluate the protective potential of EPOR/CD131 (heterodimeric erythropoietin receptor) stimulation in the neurodegeneration caused by rotenone-induced mitochondrial dysfunction. The effects of erythropoietin (EPO) and an EPO mimetic peptide pHBSP were assessed using in vivo and in vitro models. Single injections of 10 µg/kg EPO or 5 µg/kg pHBSP significantly alleviated the degeneration of ganglion cells of the retina in a rotenone-induced retinopathy in rats (p < 0.05). Consistently, in vitro exposure of rotenone-treated murine primary neuroglial cultures to 500 nM EPO or pHBSP significantly rescued the survival of the cells (p < 0.005). The observed enhancement of LC3A, ATG7, Beclin-1, Parkin and BNIP3 mRNA expression by EPOR/CD131 agonists implicates the autophagy and mitophagy activation as a plausible mitoprotective mechanism.

Keywords: erythropoietin, mitochondrial dysfunction, rotenone-induced retinopathy, EPOR/CD131 receptors, pHBSP