CCAAT/enhancer-binding protein δ contributes to myofibroblast transdifferentiation and renal disease progression

Abstract

Myofibroblasts are pivotal participants in pathologic processes in a wide variety of organs, such as lung, liver, and kidney, by producing several inflammatory cytokines and extracellular matrices. The mechanism by which transdifferentiation from original cell to myofibroblast occurs, however, is still unclear. The expression of smooth muscle α-actin (SMαA) is the most characteristic feature of myofibroblasts; therefore, it was speculated that any factors that promote SMαA expression might be the key to transdifferentiation to myofibroblasts and disease exacerbation. A transcription factor CCAAT/enhancer-binding protein δ (C/EBPδ) was identified and demonstrated to bind to sequences including the CArG motif from SMαA intron 1 and to increase transcriptional activity of this promoter. Expression of SMαA and C/EBPδ in the glomerular area was upregulated in rat anti-Thy1 glomerulonephritis and mouse Habu-venom glomerulonephritis, both of which are models of mesangioproliferative glomerulonephritis. In the latter model, C/EBPδ knockout mice demonstrated significantly less SMαA expression in the glomerular area on day 8 and less renal functional deterioration on day 14, compared with wild-type mice. These data suggest an important role for C/EBPδ in myofibroblast transdifferentiation and glomerulonephritis exacerbation.