Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease

Kidney Int. 2016 Aug;90(2):300-310. doi: 10.1016/j.kint.2016.02.018. Epub 2016 Apr 27.

Abstract

Recent work demonstrates that Alport glomerular disease is mediated through a biomechanical strain-sensitive activation of mesangial actin dynamics. This occurs through a Rac1/CDC42 cross-talk mechanism that results in the invasion of the subcapillary spaces by mesangial filopodia. The filopodia deposit mesangial matrix proteins in the glomerular basement membrane, including laminin 211, which activates focal adhesion kinase in podocytes culminating in the up-regulation of proinflammatory cytokines and metalloproteinases. These events drive the progression of glomerulonephritis. Here we test whether endothelial cell-derived endothelin-1 is up-regulated in Alport glomeruli and further elevated by hypertension. Treatment of cultured mesangial cells with endothelin-1 activates the formation of drebrin-positive actin microspikes. These microspikes do not form when cells are treated with the endothelin A receptor antagonist sitaxentan or under conditions of small, interfering RNA knockdown of endothelin A receptor mRNA. Treatment of Alport mice with sitaxentan results in delayed onset of proteinuria, normalized glomerular basement membrane morphology, inhibition of mesangial filopodial invasion of the glomerular capillaries, normalization of glomerular expression of metalloproteinases and proinflammatory cytokines, increased life span, and prevention of glomerulosclerosis and interstitial fibrosis. Thus endothelin A receptor activation on mesangial cells is a key event in initiation of Alport glomerular disease in this model.

Keywords: Alport syndrome; actin dynamics; endothelin; glomerulonephritis.

Publication types

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

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Endothelin Receptor Antagonists / pharmacology
  • Endothelin Receptor Antagonists / therapeutic use
  • Endothelin-1 / metabolism*
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Glomerular Basement Membrane / metabolism
  • Hypertension / metabolism
  • Isoxazoles / pharmacology
  • Isoxazoles / therapeutic use
  • Laminin / metabolism
  • Mesangial Cells / drug effects
  • Mesangial Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nephritis, Hereditary / genetics
  • Nephritis, Hereditary / metabolism*
  • Podocytes / metabolism*
  • Proteinuria / drug therapy
  • Pseudopodia / physiology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptor, Endothelin A / genetics
  • Receptor, Endothelin A / metabolism*
  • Signal Transduction
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use
  • Up-Regulation

Substances

  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Isoxazoles
  • Laminin
  • RNA, Small Interfering
  • Receptor, Endothelin A
  • Thiophenes
  • sitaxsentan