Glomerular Endothelial Cells as Instigators of Glomerular Sclerotic Diseases

Abstract

Glomerular endothelial cell (GEnC) dysfunction is important in the pathogenesis of glomerular sclerotic diseases, including Focal Segmental Glomerulosclerosis (FSGS) and overt diabetic nephropathy (DN). GEnCs form the first cellular barrier in direct contact with cells and factors circulating in the blood. Disturbances in these circulating factors can induce GEnC dysfunction. GEnC dysfunction occurs in early stages of FSGS and DN, and is characterized by a compromised endothelial glycocalyx, an inflammatory phenotype, mitochondrial damage and oxidative stress, aberrant cell signaling, and endothelial-to-mesenchymal transition (EndMT). GEnCs are in an interdependent relationship with podocytes and mesangial cells, which involves bidirectional cross-talk via intercellular signaling. Given that GEnC behavior directly influences podocyte function, it is conceivable that GEnC dysfunction may culminate in podocyte damage, proteinuria, subsequent mesangial activation, and ultimately glomerulosclerosis. Indeed, GEnC dysfunction is sufficient to cause podocyte injury, proteinuria and activation of mesangial cells. Aberrant gene expression patterns largely contribute to GEnC dysfunction and epigenetic changes seem to be involved in causing aberrant transcription. This review summarizes literature that uncovers the importance of cross-talk between GEnCs and podocytes, and GEnCs and mesangial cells in the context of the development of FSGS and DN, and the potential use of GEnCs as efficacious cellular target to pharmacologically halt development and progression of DN and FSGS.

Serum Albumin in Health and Disease: Esterase, Antioxidant, Transporting and Signaling Properties

“…However, dysfunction of the glomerular endothelium is characterized not only by damage to the endothelial glycocalyx and oxidative stress in ECs, but also by the endothelial–mesenchymal transition (EndMT) [ 244 ]. EndMT is a process by which ECs lose their endothelial phenotype (e.g., decreased expression of EC markers CD31 and CD144) and endothelial-specific functional characteristics (atrombogenicity, barrier functions).…”

Molecular Mechanisms in Early Diabetic Kidney Disease: Glomerular Endothelial Cell Dysfunction

“…Increased ROS production and accumulation of ROS damage products promote injury in all glomerular cells, especially in GECs, resulting in dysfunction. Impaired endothelial function in DKD is now recognized to cause functional and structural changes within the glomerulus through crosstalk [ 20 , 138 , 171 ], and this may be central to early pathogenesis and help drive disease progression. Though being generated from many sources in diabetes, ROS from NADPH oxidase, XORs and mitochondria are thought to cause the onset of albuminuria followed by a progression of renal damage.…”

“…There are several alterations in podocyte structure and function associated with FPE in DKD, including dedifferentiation (epithelial-to-mesenchymal transition), cytoskeletal rearrangement, impaired autophagy and apoptosis, which have been reviewed elsewhere [ 15 , 16 , 17 , 18 ]. Although podocytes have been studied extensively as primary targets in DKD, more recently, GEC dysfunction has been attributed to the pathogenesis of glomerular sclerotic diseases, including DKD [ 19 , 20 , 21 , 22 ].…”

Therapeutic trials in adult FSGS: lessons learned and the road forward

“…Even more commonly, mutations in the structural GBM glycoproteins of the collagen IV lineage are causes of FSGS 18 . Future studies will probably identify causative mutations in novel genes, such as those involved in mitochondrial function or maintenance of the endothelial glycocalyx 19 .…”