Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease

Abstract

Kidney International (2020) 97, 951-965; https://doi.

Roles of Endovascular Calyx Related Enzymes in Endothelial Dysfunction and Diabetic Vascular Complications

“…The administration of matrix metalloproteinase inhibitors can attenuate proteinuria. MMP inhibitor treatment also significantly increased the glycocalyx depth of podocytes, but had no significant effect on glomerular-basement-membrane thickness, podocyte foot processes, and slit-diaphragm width (Ramnath et al, 2019). On the one hand, heparan sulfate fragments bind to CD44, and toll-like receptors 2 and 4 (Pahwa et al, 2016).…”

“…Diabetes triggers the release of inflammatory factors. Previous research indicated that, on the surface of the glomerular vascular endothelium (Yuelong et al, 2014), proinflammatory factors such as TNF-α activate mast cells and cause them to release enzymes (hyaluronidase, heparinase, MMP-9/2) (Ramnath et al, 2019;Reine et al, 2019). Then, MMP-9 can destroy the glycocalyx, and release heparan sulfate and syndecan into the blood (Ramnath et al, 2014).…”

The Role of Glycocalyx and Caveolae in Vascular Homeostasis and Diseases

“…ROS also decrease the levels of the tissue inhibitors of metalloproteinases (TIMPs), thereby increasing the activity of MMPs ( Siwik and Colucci, 2004 ). The inhibition of MMPs was able to restore the shedding of syndecan-4 in early diabetic disease ( Ramnath et al, 2020 ).…”

The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation—Where Have We Gone So Far?

“…It should be noted that MMP-mediated shedding of syndecans has been found to contribute to the endothelial glycocalyx disruption as occurs in various entities, including diabetes mellitus and other pro-inflammatory states [ 80 , 81 ]. Additionally, bilateral renal IRI in syndecan-1–deficient mice as compared to wild-type mice has been associated with augmented macrophage and myofibroblast numbers as well as tubular injury [ 82 ].…”

“…GAG chains of syndecan-1 act as binding sites for hepatocyte growth factor (HGF), and mediate HGF interaction with its specific receptor, the mesenchymal epithelial transition factor (c-Met). In turn, HGF receptor together with its downstream effectors, AKT and glycogen synthase kinase-3β (GSK-3β) have been shown to play a renoprotective role in AKI [ 81 , 84 ]. Pharmacological inhibition of syndecan-1 shedding in the setting of IRI activates phosphorylation of the c-Met/AKT/GSK-3β signaling pathway, thus further supporting the important role of syndecan-1 as a coreceptor for HGF to attenuate apoptosis and inflammation in IRI [ 85 ].…”