Diabetic nephropathy is the leading cause of
end-stage renal disease.
Diabetes mellitus is characterized by generalized endothelial dysfunction. However, recent data also emphasizes the role of local renal endothelium dysfunction in the pathogenesis of
diabetic nephropathy.
Hyperglycemia triggers a complex network of signal-transduction molecules,
transcription factors, and mediators that culminate in endothelial dysfunction. In the glomerulus,
vascular endothelial growth factor-A (
VEGF)-induced neoangiogenesis may contribute to the initial hyperfiltration and microalbuminuria due to increased filtration area and immaturity of the neovessels, respectively. However, subsequent decrease in podocytes number decreases
VEGF production resulting in
capillary rarefaction and decreased glomerular filtration rate (GFR). Decreased
nitric oxide availability also plays a significant role in the development of advanced lesions of
diabetic nephropathy through disruption of glomerular autoregulation, uncontrolled
VEGF action, release of prothrombotic substances by endothelial cells and
angiotensin-II-independent
aldosterone production. In addition, disturbances in endothelial glycocalyx contribute to decreased permselectivity and microalbuminuria; whereas there are recent evidences that reduced glomerular fenestral endothelium leads to decreased GFR levels. Endothelial repair mechanisms are also impaired in diabetes, since circulating endothelial progenitor cells number is decreased in diabetic patients with microalbuminuria. Finally, in the context of elevated profibrotic
cytokine transforming growth factor-β levels, endothelial cells also confer to the deteriorating process of
fibrosis in advanced
diabetic nephropathy through endothelial to mesenchymal transition.