Gamma-Aminobutyric Acid Increases Erythropoietin by Activation of Citrate Cycle and Stimulation of Hypoxia-Inducible Factors Expression in Rats

Abstract

Erythropoietin (EPO) is the primary regulator of erythropoiesis in the mammalian fetus and adult. Deficiency of EPO induces anemia. In this study, we investigated the effect of gamma-aminobutyric acid (GABA) on serum EPO levels and erythropoiesis in rats. Expression levels of Epo-related genes were measured by quantitative real-time PCR (qPCR) and expression of Epo and Epo receptor (Epor) proteins were measured by immunohistochemistry. The gene and protein expression profiles of kidney tissue in GABA-treated rats were evaluated by ribonucleic acid (RNA) sequencing and two-dimensional electrophoresis (2-DE), respectively. GABA significantly increased serum EPO levels and expression levels of Epo and Epor. GABA increased expression levels of hypoxia-inducible factor (Hif)-1 and Hif-2. Seven proteins with expression levels showing >2-fold change were identified by 2-DE followed by MALDI-TOF MS in GABA-treated rat kidney. The top KEGG pathway from the identified proteins was the tricarboxylic acid cycle, and nicotinamide adenine dinucleotide (NADH) dehydrogenase, succinate dehydrogenase, and isocitrate dehydrogenase were identified as key proteins. GABA treatment significantly increased ATP levels and NADH dehydrogenase activity in a dose-dependent manner. In conclusion, GABA shows a new physiological role in EPO production, and it can thus can contribute to the prevention of anemia when used alone or in combination with other anemia treating drugs.