Early diabetic kidney disease: Focus on the glycocalyx

Abstract

The incidence of diabetic kidney disease (DKD) is sharply increasing worldwide. Microalbuminuria is the primary clinical marker used to identify DKD, and its initiating step in diabetes is glomerular endothelial cell dysfunction, particularly glycocalyx impairment. The glycocalyx found on the surface of glomerular endothelial cells, is a dynamic hydrated layer structure composed of pro-teoglycans, glycoproteins, and some adsorbed soluble components. It reinforces the negative charge barrier, transduces the shear stress, and mediates the interaction of blood corpuscles and podocytes with endothelial cells. In the high-glucose environment of diabetes, excessive reactive oxygen species and proinflammatory cytokines can damage the endothelial glycocalyx (EG) both directly and indirectly, which induces the production of microalbuminuria. Further research is required to elucidate the role of the podocyte glycocalyx, which may, together with endothelial cells, form a line of defense against albumin filtration. Interestingly, recent research has confirmed that the negative charge barrier function of the glycocalyx found in the glomerular basement membrane and its repulsion effect on albumin is limited. Therefore, to improve the early diagnosis and treatment of DKD, the potential mechanisms of EG degradation must be analyzed and more responsive and controllable targets must be explored. The content of this review will provide insights for future research.

Keywords: Diabetic kidney disease; Endothelial cells; Enzyme; Glycocalyx; Microalbuminuria; Reactive oxygen species.

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.