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Divergent regulation of sense and antisense erythropoietin receptor transcripts (asEPOR) in obesity‐associated diabetes mellitus
Author(s) -
Hsia Connie C.W.,
Esser Victoria,
Ravikumar Priya,
Unger Roger H,
Moe Orson W.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1062.2
Subject(s) - erythropoietin receptor , endocrinology , medicine , erythropoietin , angiogenesis , biology , receptor , type 2 diabetes mellitus , lung , diabetes mellitus
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