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Abstract: PO0893

Glomerular Endothelial Glycocalyx Damage Occurs in Human Diabetic Nephropathy and Could Be Prevented by Early Mineralocorticoid Receptor Inhibition

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Crompton, Michael, University of Bristol, Bristol, United Kingdom
  • Butler, Matthew J., University of Bristol, Bristol, United Kingdom
  • Onions, Karen L., University of Bristol, Bristol, United Kingdom
  • Ogier, Anna S., University of Bristol, Bristol, United Kingdom
  • Welsh, Gavin Iain, University of Bristol, Bristol, United Kingdom
  • Foster, Rebecca R., University of Bristol, Bristol, United Kingdom
  • Satchell, Simon C., University of Bristol, Bristol, United Kingdom

Group or Team Name

  • Bristol Renal
Background

The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the filtration barrier. In rodent models, damage to the GEnGlx occurs early in the pathogenesis of diabetic nephropathy (DN). Until now no techniques have been available to quantify GEnGlx damage in human disease. Mineralocorticoid receptor (MR) antagonists slow disease progression, but side effects limit their clinical use. We aimed to develop a method to study GEnGlx changes in human disease and investigate whether MR inhibition could preserve the GEnGlx in a rat DN model.

Methods

Human renal biopsies from patients with DN and thin basement membrane disease (TBMD) were analysed using our novel peak-to-peak confocal imaging method (UEA-I lectin) to assess GEnGlx depth. Male Wistar rats injected with streptozotocin (50mg/kg I.P.) were used to study if spironolactone (50mg/kg daily S.C.), an MR inhibitor, could preserve the GEnGlx and limit the development of DN. Our glomerular permeability assay was used to directly measure the albumin permeability (Ps’alb), in isolation from haemodynamic changes. Peak-to-peak (WGA lectin) was validated against electron microscopy GEnGlx depth measurements. MMP2 activity was quantified using a specific activity assay and ELISAs were used to measure urine albumin levels.

Results

In human DN, GEnGlx depth was reduced compared to patients with TBMD (p=0.013). Diabetic rats developed albuminuria and the Ps’alb increased 1.6-fold (p<0.001). Again, GEnGlx depth was reduced in DN compared to controls (p<0.001). Plasma and urinary active MMP2 were increased (p=0.017 and p<0.001). MR blockade preserved the GEnGlx, restored Ps’alb to control values and prevented albuminuria progression. Reduced urinary active MMP2 (p=0.012) and glomerular Mmp2 mRNA expression (p=0.002) were seen following MR blockade in DN. GEnGlx enzymatic degradation, with hyaluronidase, reversed the effect of MR blockade in DN confirming the importance of GEnGlx preservation in this model.

Conclusion

MR blockade in DN preserves the GEnGlx, reduces Ps’alb and retards the development of albuminuria. Alternative approaches to block MR-induced GEnGlx damage represent a novel potential therapeutic strategy, to reproduce the benefit of MR antagonists without adverse side effects.