Early diabetic kidney disease: Focus on the glycocalyx

Figure 1 The glycocalyx in the physiological state and the diabetic microenvironment. Under normal physiological conditions, endothelial glycocalyx shedding and recovery are in a state of equilibrium, which can form an albumin exclusion barrier on the endothelial surface. However, in the diabetic microenvironment, inflammation, oxidative stress, and other harmful factors can not only directly destroy the glycocalyx but also hydrolyze the glycocalyx by activating the related sheddases, such as heparinase (HPSE), hyaluronidase, matrix metalloproteinases (MMPs), and neuraminidase, resulting in the shedding of a large number of glycocalyx components, leukocyte and platelet adhesion, macrophage infiltration, and microalbuminuria. In addition, the interaction between podocytes and endothelial cells plays a vital role in glycocalyx degradation. For example, the production of vascular endothelial growth factor A₁₆₅ (VEGF-A₁₆₅) by podocytes acts on VEGF receptor 2 (VEGER2) in endothelial cells to induce the production of MMPs. Angiopoietin-2 (Ang-2) acts on Tie2 to increase the expression of HPSE, and Ang-2 also upregulates VEGF-A₁₆₅ to degrade the glycocalyx further. In addition, there is an interaction between Tie2 and VEGER2. Endothelin-1 acts on endothelial cells Ednra to produce reactive oxygen species; it also acts on Ednra/Ednrb in podocytes to induce the production of HPSE to degrade the glycocalyx. HA: Hyaluronic acid; CS: Chondroitin sulfate; HS: Heparin sulfate; SA: Sialic acids; HPSE: Heparinase; MMPs: Matrix metalloproteinases; HYAL: Hyaluronidase; NEU: Neuraminidase; ROS: Reactive oxygen species; VEGF-A₁₆₅: Vascular endothelial growth factor A₁₆₅; VEGFR-2: Vascular endothelial growth factor receptor 2; ET-1: Endothelin-1; Ednra: Endothelin receptor type A; Ednrb: Endothelin receptor type B; Ang-2: Angiopoietin-2; SOD: Superoxide dismutase; AT III: Antithrombin III; ICAM: Intercellular adhesion molecule; VCAM: Vascular cell adhesion molecule; EG: Endothelial glycocalyx; GBM: Glomerular basement membrane; ESL: Endothelial surface layer; SD: Slit diaphragm.