Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease

Nat Commun. 2021 Jul 27;12(1):4548. doi: 10.1038/s41467-021-24799-x.


Autosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a "cystic extracellular vesicles/exosomes theory". We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Animals
  • Benzylidene Compounds / pharmacology
  • Cell Line
  • Cell Proliferation / drug effects
  • Collagen
  • Cysts / pathology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Exosomes / drug effects
  • Exosomes / metabolism*
  • Fibrosis
  • Gene Expression Regulation / drug effects
  • Kidney / pathology*
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Models, Biological
  • Mutation / genetics
  • Polycystic Kidney, Autosomal Dominant / genetics
  • Polycystic Kidney, Autosomal Dominant / pathology*
  • Polycystic Kidney, Autosomal Dominant / urine
  • Rats
  • Signal Transduction / drug effects
  • TRPP Cation Channels / metabolism
  • Tetraspanin 30 / metabolism


  • Aniline Compounds
  • Benzylidene Compounds
  • GW 4869
  • MicroRNAs
  • TRPP Cation Channels
  • Tetraspanin 30
  • polycystic kidney disease 1 protein
  • Collagen