Glomerular endothelial cell injury and cross talk in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) remains a leading cause of new-onset end-stage renal disease (ESRD), and yet, at present, the treatment is still very limited. A better understanding of the pathogenesis of DKD is therefore necessary to develop more effective therapies. Increasing evidence suggests that glomerular endothelial cell (GEC) injury plays a major role in the development and progression of DKD. Alteration of the glomerular endothelial cell surface layer, including its major component, glycocalyx, is a leading cause of microalbuminuria observed in early DKD. Many studies suggest a presence of cross talk between glomerular cells, such as between GEC and mesangial cells or GEC and podocytes. PDGFB/PDGFRβ is a major mediator for GEC and mesangial cell cross talk, while vascular endothelial growth factor (VEGF), angiopoietins, and endothelin-1 are the major mediators for GEC and podocyte communication. In DKD, GEC injury may lead to podocyte damage, while podocyte loss further exacerbates GEC injury, forming a vicious cycle. Therefore, GEC injury may predispose to albuminuria in diabetes either directly or indirectly by communication with neighboring podocytes and mesangial cells via secreted mediators. Identification of novel mediators of glomerular cell cross talk, such as microRNAs, will lead to a better understanding of the pathogenesis of DKD. Targeting these mediators may be a novel approach to develop more effective therapy for DKD.

Keywords: angiopoietin; diabetes; endothelial cells; endothelial nitric oxide; endothelial surface layer; endothelin-1; fenestrate; glomerular filtration barrier; glycocalyx; hepatocyte growth factor; insulin-like growth factor; microRNA; prostanoids; proteoglycans; vascular endothelial growth factor.

Copyright © 2015 the American Physiological Society.

Figures

Fig. 1.

Normal glomerular filtration barrier complex and its disruption in diabetic kidney disease. A: schematic illustration of the normal glomerular filtration barrier complex, consisting of podocyte foot processes with their slit diaphragm, glomerular basement membrane (GBM), and the glomerular surface layer (ESL). Glomerular endothelium and fenestrae are covered by the glycocalyx, a meshwork of membrane-bound glycoproteins and proteoglycans. Cell-to-cell communication occurs through a bidirectional diffusion of cytokines/growth factors produced by one or more of the glomerular cell types. B: schematic illustration of a diabetic kidney, which is characterized by GBM thickening, mesangial expansion, and podocyte foot process effacement and detachment. In addition, the fenestrated area of endothelial cells is reduced, the amount of glycocalyx is diminished, and the communication between glomerular endothelial cells (GEC) and neighboring glomerular cells is altered. The abnormal renal expression of VEGF, angiopoetins, and endothelin-1 in early diabetic kidney disease (DKD) induces neoangiogenesis and may contribute to the initial hyperfiltration. GEC also produce other mediators, such as HGF and IGF, and their dysregulation is associated with glomerular hypertrophy and microalbuminuria in early DKD. See th text for additional definitions.