TY - JOUR
T1 - Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease
T2 - Syndecan 4 in diabetic kidney disease
AU - Ramnath, Raina
AU - Butler, Matthew
AU - Newman, Georgina
AU - Desideri, Sara
AU - Russell, Amy
AU - Lay, Abigail
AU - Neal, Chris R
AU - Qiu, Yan
AU - Fawaz, Sarah
AU - Onions, Karen L
AU - Gamez, Monica
AU - Crompton, Michael
AU - Michie, Chris
AU - Finch, Natalie
AU - Coward, Richard J M
AU - Welsh, Gavin Iain
AU - Foster, Rebecca
AU - Satchell, Simon C
PY - 2019/11/2
Y1 - 2019/11/2
N2 - The endothelial glycocalyx is a key component of the glomerular filtration barrier. We have shown that matrix metalloproteinase (MMP)-mediated syndecan 4 shedding is a mechanism of glomerular endothelial glycocalyx damage in vitro, resulting in increased albumin permeability. Here we sought to determine whether this mechanism is important in diabetes in vivo. We studied early diabetic kidney disease in streptozotocin-induced type 1 diabetes in DBA2/J mice. Diabetic mice were albuminuric and had increased glomerular albumin permeability and endothelial glycocalyx damage. Syndecan 4 mRNA expression was upregulated in isolated glomeruli and flow cytometry-sorted glomerular endothelial cells. In contrast, glomerular endothelial luminal surface syndecan 4 and Marasmium oreades agglutinin lectin labelling measurements were reduced in diabetes. Similarly, syndecan 4 protein expression was significantly decreased in isolated glomeruli and increased in plasma and urine, suggesting syndecan 4 shedding. MMP 2, 9 and 14 mRNA expression were upregulated in isolated glomeruli, suggesting a possible mechanism of glycocalyx damage and albuminuria. We therefore characterised in detail the activity of MMP 2 and 9 and showed significant increases in kidney cortex, plasma and urine. Therapeutic treatment with MMP 2/9 inhibitor I at 5mg/kg/day for 21 days, started 6 weeks after diabetes induction, restored endothelial glycocalyx depth and coverage and attenuated diabetes-induced albuminuria and reduced glomerular albumin permeability. MMP inhibitor treatment significantly attenuated glomerular endothelial and plasma syndecan 4 shedding and inhibited plasma MMP activity. These studies confirm the importance of MMPs in endothelial glycocalyx damage and albuminuria in early diabetes and demonstrate that this pathway is amenable to therapeutic intervention. Treatments targeted at glycocalyx protection by MMP inhibition may be of benefit in diabetic kidney disease.
AB - The endothelial glycocalyx is a key component of the glomerular filtration barrier. We have shown that matrix metalloproteinase (MMP)-mediated syndecan 4 shedding is a mechanism of glomerular endothelial glycocalyx damage in vitro, resulting in increased albumin permeability. Here we sought to determine whether this mechanism is important in diabetes in vivo. We studied early diabetic kidney disease in streptozotocin-induced type 1 diabetes in DBA2/J mice. Diabetic mice were albuminuric and had increased glomerular albumin permeability and endothelial glycocalyx damage. Syndecan 4 mRNA expression was upregulated in isolated glomeruli and flow cytometry-sorted glomerular endothelial cells. In contrast, glomerular endothelial luminal surface syndecan 4 and Marasmium oreades agglutinin lectin labelling measurements were reduced in diabetes. Similarly, syndecan 4 protein expression was significantly decreased in isolated glomeruli and increased in plasma and urine, suggesting syndecan 4 shedding. MMP 2, 9 and 14 mRNA expression were upregulated in isolated glomeruli, suggesting a possible mechanism of glycocalyx damage and albuminuria. We therefore characterised in detail the activity of MMP 2 and 9 and showed significant increases in kidney cortex, plasma and urine. Therapeutic treatment with MMP 2/9 inhibitor I at 5mg/kg/day for 21 days, started 6 weeks after diabetes induction, restored endothelial glycocalyx depth and coverage and attenuated diabetes-induced albuminuria and reduced glomerular albumin permeability. MMP inhibitor treatment significantly attenuated glomerular endothelial and plasma syndecan 4 shedding and inhibited plasma MMP activity. These studies confirm the importance of MMPs in endothelial glycocalyx damage and albuminuria in early diabetes and demonstrate that this pathway is amenable to therapeutic intervention. Treatments targeted at glycocalyx protection by MMP inhibition may be of benefit in diabetic kidney disease.
UR - https://research-information.bris.ac.uk/en/publications/f9c27a17-6a10-4248-b4ed-5d3db7819f8b
U2 - 10.1016/j.kint.2019.09.035
DO - 10.1016/j.kint.2019.09.035
M3 - Article
C2 - 32037077
SN - 0085-2538
JO - Kidney International
JF - Kidney International
ER -
