Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells

Kidney Int. 2019 Oct;96(4):957-970. doi: 10.1016/j.kint.2019.05.007. Epub 2019 May 22.


Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-β receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondrial reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis.

Keywords: Edn1; GECs; TGF-βI; crosstalk; glomerular ESL; glycocalyx; podocytes; proteinuria.

Publication types

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

MeSH terms

  • Albuminuria / chemically induced
  • Albuminuria / drug therapy
  • Albuminuria / genetics
  • Albuminuria / pathology*
  • Animals
  • Capillaries / cytology
  • Capillaries / drug effects
  • Capillaries / pathology
  • Capillaries / ultrastructure
  • Cell Communication / drug effects*
  • Disease Models, Animal
  • Doxorubicin / toxicity
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology*
  • Endothelin A Receptor Antagonists / administration & dosage
  • Endothelin B Receptor Antagonists / administration & dosage
  • Endothelin-1 / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / ultrastructure
  • Humans
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / cytology
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / pathology*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Scanning
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Podocytes / cytology
  • Podocytes / drug effects
  • Podocytes / metabolism
  • Podocytes / pathology
  • Reactive Oxygen Species / metabolism
  • Receptor, Endothelin A / metabolism*
  • Receptor, Endothelin B / metabolism
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Receptor, Transforming Growth Factor-beta Type I / metabolism


  • EDNRB protein, mouse
  • Endothelin A Receptor Antagonists
  • Endothelin B Receptor Antagonists
  • Endothelin-1
  • Reactive Oxygen Species
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Doxorubicin
  • Receptor, Transforming Growth Factor-beta Type I
  • Tgfbr1 protein, mouse