c-Myc participates in high glucose-mediated endothelial inflammation via upregulation of IRAK1 expression in diabetic nephropathy

Cell Signal. 2022 Apr:92:110263. doi: 10.1016/j.cellsig.2022.110263. Epub 2022 Jan 24.

Abstract

Diabetic nephropathy (DN) is a common vascular complication of diabetes. Endothelial adhesion molecules are involved in physiopathology of DN. Interleukin-1 receptor-associated kinase 1 (IRAK1) and c-Myc participate in inflammation in DN. We hypothesized c-Myc modulates IRAK1 expression, contributing to hyperglycemia-mediated endothelial inflammation. The expression of endothelial adhesion molecules and IRAK1 were increased in glomerular endothelium of DN patients and rats. Our cellular experiments indicated high glucose-induced endothelial cell inflammation was inhibited by si-IRAK1. Additionally, high glucose increased c-Myc expression. si-c-Myc inhibited high glucose-mediated increase of IRAK1 levels and endothelial cell inflammation. c-Myc overexpression-mediated endothelial cell inflammation was counteracted by si-IRAK1. c-Myc also interacted with lysine methyltransferase 5A (KMT5A). Furthermore, high glucose decreased KMT5A expression and histone H4 lysine 20 methylation (H4K20me1). KMT5A upregulation decreased high glucose-mediated increase of IRAK1 levels as well as endothelial inflammation. KMT5A silencing-mediated endothelial inflammation was reversed by si-IRAK1. Mechanistic research indicated that c-Myc and H4K20me1 occupied IRAK1 promoter region. KMT5A silencing augmented the active action of c-Myc on IRAK1 levels. Our in vivo experiments represented KMT5A is downregulated and c-Myc is upregulated in DN patients and rats. KMT5A interacts with c-Myc to modulate IRAK1 expression, thus contributing to hyperglycemia-mediated endothelial inflammation in DN.

Keywords: Diabetic nephropathy; Endothelial adhesive molecules; IRAK1; KMT5A; c-Myc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus* / pathology
  • Diabetic Nephropathies* / pathology
  • Endothelium / metabolism
  • Glucose / metabolism
  • Glucose / toxicity
  • Humans
  • Inflammation / pathology
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Rats
  • Up-Regulation

Substances

  • IRAK1 protein, human
  • IRAK1 protein, rat
  • Interleukin-1 Receptor-Associated Kinases
  • Glucose