Mineralocorticoid receptor antagonism in diabetes limits albuminuria by preserving endothelial glycocalyx

Michael Crompton, Joanne K Ferguson, Raina D Ramnath, Karen L Onions, Anna S Ogier, Colin J Down, Laura J S Skinner, Lauren Dixon, Judit Sutak, Steven J Harper, Paola Pontrelli, Loreto Gesualdo, Gavin I Welsh, R R Foster, Simon C Satchell, Matthew J Butler*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the glomerular filtration barrier (GFB). Excess mineralocorticoid receptor (MR) activation causes GEnGlx damage and albuminuria. We hypothesised that MR antagonism with spironolactone limits albuminuria in diabetes by preserving the GEnGlx. Streptozotocin-induced diabetic Wistar rats developed increased glomerular albumin permeability (Ps’alb) and albuminuria, with associated GEnGlx loss and increased plasma and urine active MMP2. Spironolactone reduced MMP2 activity, preserved the GEnGlx, restored Ps’alb to control values and prevented diabetes-induced albuminuria progression. Enzymatic degradation of the GEnGlx, with hyaluronidase, reversed the effect of spironolactone in diabetic rats, confirming the importance of GEnGlx preservation in this model. Previously, no techniques have been available to directly quantify GEnGlx damage in human disease. We validated a novel fluorescent profile peak-to-peak confocal imaging technique and applied it to assess GEnGlx damage on renal biopsies from patients with DN and compared them to healthy controls. We confirmed that dramatic GEnGlx loss occurs in human DN. This likely contributes to the increased glomerular albumin permeability seen in human DN. Taken together our work suggests GEnGlx preservation is an important mechanism of reno-protection by MR inhibitors in diabetes.
Original languageEnglish
JournalJournal of the American Society of Nephrology
Publication statusIn preparation - 1 Sept 2020

Structured keywords

  • Bristol Heart Institute

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