MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

Exp Cell Res. 2015 Apr 10;333(1):155-63. doi: 10.1016/j.yexcr.2015.01.018. Epub 2015 Feb 7.

Abstract

Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, and chemokine (C-C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss.

Keywords: Acute renal allograft rejection; BCL2L11; Endothelial cells; Inflammatory cytokines; microRNA.

MeSH terms

  • Allografts
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Base Sequence*
  • Bcl-2-Like Protein 11
  • Binding Sites
  • Case-Control Studies
  • Cells, Cultured
  • Chemokines / metabolism
  • Chemotaxis
  • Down-Regulation
  • Graft Rejection / genetics
  • Graft Rejection / immunology
  • Graft Rejection / metabolism*
  • Humans
  • Kidney Transplantation
  • Macrophages / physiology
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Chemokines
  • MIRN10 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Proto-Oncogene Proteins