Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis

Nat Commun. 2020 Apr 23;11(1):1943. doi: 10.1038/s41467-020-15732-9.

Abstract

Kidney fibrosis is a highly deleterious process and a final manifestation of chronic kidney disease. Alpha-(α)-synuclein (SNCA) is an actin-binding neuronal protein with various functions within the brain; however, its role in other tissues is unknown. Here, we describe the expression of SNCA in renal epithelial cells and demonstrate its decrease in renal tubules of murine and human fibrotic kidneys, as well as its downregulation in renal proximal tubular epithelial cells (RPTECs) after TGF-β1 treatment. shRNA-mediated knockdown of SNCA in RPTECs results in de novo expression of vimentin and α-SMA, while SNCA overexpression represses TGF-β1-induced mesenchymal markers. Conditional gene silencing of SNCA in RPTECs leads to an exacerbated tubulointerstitial fibrosis (TIF) in two unrelated in vivo fibrotic models, which is associated with an increased activation of MAPK-p38 and PI3K-Akt pathways. Our study provides an evidence that disruption of SNCA signaling in RPTECs contributes to the pathogenesis of renal TIF by facilitating partial epithelial-to-mesenchymal transition and extracellular matrix accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Cell Line
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Fibrosis
  • Gene Expression / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Kidney / metabolism
  • Kidney / pathology*
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta1 / pharmacology
  • Ureteral Obstruction / genetics
  • Ureteral Obstruction / metabolism
  • Ureteral Obstruction / pathology
  • Vimentin / genetics
  • Vimentin / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • ACTA2 protein, human
  • Actins
  • Protein Kinase Inhibitors
  • SNCA protein, human
  • Transforming Growth Factor beta1
  • VIM protein, human
  • Vimentin
  • alpha-Synuclein
  • Proto-Oncogene Proteins c-akt
  • MAPK1 protein, human
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases