Aldosterone induces albuminuria via matrix metalloproteinase–dependent damage of the endothelial glycocalyx

Matthew J. Butler*, Raina Ramnath, Hiroyuki Kadoya, Dorinne Desposito, Anne Riquier-Brison, Joanne K. Ferguson, Karen L. Onions, Anna S. Ogier, Hesham ElHegni, Richard J. Coward, Gavin I. Welsh, Rebecca R. Foster, Janos Peti-Peterdi, Simon C. Satchell

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

5 Citations (Scopus)
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Abstract

Aldosterone contributes to end-organ damage in heart failure and chronic kidney disease. Mineralocorticoid-receptor inhibitors limit activation of the receptor by aldosterone and slow disease progression, but side effects, including hyperkalemia, limit their clinical use. Damage to the endothelial glycocalyx (a luminal biopolymer layer) has been implicated in the pathogenesis of endothelial dysfunction and albuminuria, but to date no one has investigated whether the glomerular endothelial glycocalyx is affected by aldosterone. In vitro, human glomerular endothelial cells exposed to 0.1 nM aldosterone and 145 mMol NaCl exhibited reduced cell surface glycocalyx components (heparan sulfate and syndecan-4) and disrupted shear sensing consistent with damage of the glycocalyx. In vivo, administration of 0.6 μg/g/d of aldosterone (subcutaneous minipump) and 1% NaCl drinking water increased glomerular matrix metalloproteinase 2 activity, reduced syndecan 4 expression, and caused albuminuria. Intravital multiphoton imaging confirmed that aldosterone caused damage of the glomerular endothelial glycocalyx and increased the glomerular sieving coefficient for albumin. Targeting matrix metalloproteinases 2 and 9 with a specific gelatinase inhibitor preserved the glycocalyx, blocked the rise in glomerular sieving coefficient, and prevented albuminuria. Together these data suggest that preservation of the glomerular endothelial glycocalyx may represent a novel strategy for limiting the pathological effects of aldosterone.

Original languageEnglish
Pages (from-to)94-107
Number of pages14
JournalKidney International
Volume95
Issue number1
Early online date31 Oct 2018
DOIs
Publication statusPublished - Jan 2019

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Keywords

  • aldosterone
  • albuminuria
  • endothelium
  • inflammation
  • cardiovascular disease

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