AP-1 regulates sphingosine kinase 1 expression in a positive feedback manner in glomerular mesangial cells exposed to high glucose

摘要: Abstract Our previous studies have confirmed that the sphingosine kinase 1 (SphK1)–sphingosine 1-phosphate (S1P) signaling pathway in kidney under diabetic conditions is closely correlated with pathogenesis of nephropathy (DN). The activation SphK1–S1P by high glucose (HG) can increase expression fibronectin (FN), an important fibrotic component, glomerular mesangial cells (GMCs) promoting DNA-binding activity transcription factor AP-1. However, mechanism responsible for sustained remains unclear. Given binding motifs AP-1 within first intron SphK1 gene, we speculated activated HG condition possibly regulates a positive feedback manner, thereby and mediating pathological progression DN. Here, observed effect on GMCs explored molecular involved pathway. We found two consensus promoter sequences non-coding region downstream transcriptional initiation rat gene chromatin immunoprecipitation assay. treatment both S1P significantly increased protein c-Jun c-Fos, obviously enhanced phosphorylation at Ser63 Ser73, c-Fos Ser32. Knockdown siRNAs substantially inhibited FN, whereas overexpression FN. Curcumin greatly decreased levels c-Jun, SphK1, FN tissues rats. SiRNAs targeting S1P2 receptor respectively (ser63 ser73) (ser32), as well normal conditions. data demonstrated associated to form loop. This loop functions basis lead