Early mineralocorticoid receptor antagonism in diabetic nephropathy limits albuminuria by preserving the glomerular endothelial glycocalyx
| Autor: | Matthew J. Butler, Gavin I. Welsh, Steve J Harper, Joanne K. Ferguson, Raina D. Ramnath, Loreto Gesualdo, Anna S. Ogier, Rebecca R. Foster, Paola Pontrelli, Crompton M, Karen L. Onions, Simon C. Satchell, Skinner L, Sutak J, Dixon Lk, Colin J. Down |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
business.industry medicine.disease Glycocalyx Pathogenesis Diabetic nephropathy chemistry.chemical_compound Endocrinology Mineralocorticoid receptor chemistry Diabetes mellitus Internal medicine Spironolactone Albuminuria Glomerular Filtration Barrier Medicine medicine.symptom business |
| DOI: | 10.1101/2021.05.13.21252519 |
| Popis: | The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the glomerular filtration barrier (GFB). We have previously shown that excess mineralocorticoid receptor (MR) activation causes GEnGlx damage and albuminuria. Damage to the GEnGlx occurs early in the pathogenesis of diabetic nephropathy (DN). Here we sought to determine whether MR antagonism with spironolactone could prevent the development of albuminuria in diabetes, by preserving the GEnGlx to maintain the GFB. Streptozotocin-induced diabetic Wistar rats developed increased glomerular albumin permeability (Ps’alb) and albuminuria, with associated GEnGlx loss and increases in plasma and urine active matrix metalloproteinase 2 (MMP2). MR antagonism reduced urine active MMP2, 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 MR antagonism in diabetic rats, confirming the importance of GEnGlx preservation in this model. Using this model 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 GEnGlx loss occurs in human DN and may contribute to the disease phenotype. Taken together our work suggests GEnGlx preservation as an important novel mechanism for reno-protection by MR inhibitors in diabetes.Translational StatementMineralocorticoid receptor (MR) antagonists reduce albuminuria in diabetic nephropathy (DN), but side effects limit their clinical utility, and the mechanism is unknown. This paper demonstrates that MR antagonism prevented the development of glomerular endothelial glycocalyx (GEnGlx) dysfunction and albuminuria. Highly specific, enzyme mediated, removal of the GEnGlx abolished this effect, confirming the importance of EnGlx preservation in this model. Our data also confirm that GEnGlx damage occurs in human DN and may contribute to the clinical phenotype. This work suggests directly targeting glycocalyx preservation in DN could reproduce the protective effects seen with MR inhibition, whilst avoiding side effects. |
| Databáze: | OpenAIRE |
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