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Endothelin-1 Induces Proteinuria by Heparanase-Mediated Disruption of the Glomerular Glycocalyx

Marjolein Garsen1, Olivia Lenoir2, Angelique L W M M Rops1

  • 1Departments of Nephrology.

Journal of the American Society of Nephrology : JASN
|March 31, 2016
PubMed

Insights

Endothelin-1 signaling in diabetic nephropathy (DN) activates podocytes to release heparanase, damaging the kidney. Blocking endothelin receptors may prevent this damage, offering a new therapeutic strategy for chronic kidney disease (CKD).

Area of Science:

  • Nephrology
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetic nephropathy (DN) is a primary cause of chronic kidney disease (CKD).
  • Endothelin receptor antagonists show promise for DN treatment, but their mechanism is unclear.
  • Heparanase and endothelin-1 are crucial in DN development.

Purpose of the Study:

  • To investigate the role of endothelin-1 and heparanase in DN.
  • To elucidate the mechanism of action for endothelin receptor blockers in DN.

Main Methods:

  • Investigated endothelin-1-induced heparanase release from podocytes in vitro.
  • Assessed glomerular transendothelial albumin passage using conditioned podocyte medium.
  • Utilized podocyte-specific endothelin receptor knockout mice to study DN progression.

Main Results:

  • Endothelin-1 activates podocytes to release heparanase, increasing albumin passage.
  • Podocyte-specific endothelin receptor knockout prevented diabetes-induced heparanase increase, glycocalyx damage, and proteinuria.
  • Data indicate endothelin-1 signaling drives heparanase expression, glycocalyx damage, and renal failure in DN.

Conclusions:

  • Endothelin-1 signaling in podocytes contributes to DN pathogenesis via heparanase.
  • Targeting endothelin receptors may prevent DN progression by inhibiting heparanase-mediated damage.
  • This study reveals a key mechanism for endothelin receptor blocker efficacy in DN.

Keywords:
diabetic nephropathyglomerular endothelial cellsglomerular filtration barrierpodocyteproteinuria

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