Divergent regulation of sense and antisense erythropoietin receptor transcripts (asEPOR) in obesity‐associated diabetes mellitus

Abstract

Paracrine/endocrine EPO-EPOR signaling promotes angiogenesis, cytoprotection and injury-repair. Bi-directional EPOR transcription produces abundant asEPOR containing putative open reading frames (e.g., ORF1 and 2). We previously reported non-developmentally up-regulated asEPOR expression in lungs undergoing compensatory growth and angiogenesis (Proc Natl Acad Sci USA 2008;105:7612–7). To examine if EPO-EPOR axis and asEPOR also respond to chronic lung injury-repair, we measured EPO and EPOR mRNA, and asEPOR ORF1 and ORF2, normalized to cyclophilin, in the lungs of leptin-insensitive ZDF fa/fa rats that develop obesity and type-2 diabetes mellitus (T2DM) and exhibit age-related abnormalities in lung structure and function (Am J Physiol Lung Cell Mol Physiol 2010;298:L392-L403, J Appl Physiol 2010;109:1913–9) compared to lean non-diabetic (+/+) controls (ages 6, 12, 18, 36wk, n=3–7 each). Mean±SD. p≤0.05 * vs. +/+, † vs. 6 or 12wk, § vs. 36wk. In fa/fa lungs before onset of T2DM (age <12 wk), EPO and EPOR mRNA was ~34% of that in +/+ lungs while ORF2 was normal to modestly higher. After onset of T2DM, EPO and EPOR mRNA increased up to 3-fold to reach +/+ levels while ORF2 increased 14-fold above +/+ levels. ORF1 was unchanged with age or genotype. Results suggest divergent regulation of sense EPO-EPOR and ORF2 in the lungs exposed to chronic lipo-oxidative stress: EPO-EPOR mRNA expression is suppressed during postnatal maturation. T2DM onset is associated with catch-up EPO-EPOR expression and marked progressive ORF2 up-regulation. Support: NIH NCI R21 CA152977, NHLBI RO1 HL40070