The Renal Endothelium in Diabetic Nephropathy

Abstract

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.

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

“…However, in the late stage of DM, VEGF expression decreases, perhaps due to a decreased number of podocytes, resulting in fewer renal capillaries and a reduced GFR. Anti-VEGF therapy is effective in an early DKD model [29]. In the present study, we found that the serum VEGF level in the DKD patients (1.28±0.23 ng/ ml) was significantly higher than that in the DM patients without urinary protein excretion (0.94±0.21 ng/ml); additionally, VEGF was positively correlated with 24 h urinary protein, in agreement with the results of the above study.…”

Autophagy in kidney disease and aging: lessons from rodent models

“…[182][183][184][185] Interestingly, the treatment of diabetic mice with resveratrol, a well-known inducer of autophagy, protects from intraglomerular capillary rarefaction, suggesting that resveratrol attenuates DN by modulating angiogenesis. 186 Moreover, autophagy protects from high glucose-induced senescence in cord human venous endothelial cells.…”

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

“…[2][3][4] Progressive and irreversible microvascular damage and loss are observed in the diabetic kidney, and a decrease in the function and density of intrarenal microvessels has been reported in several studies. [5][6][7][8] Furthermore, progressive podocyte injury, characterized by low microvessel density and number, hypertrophy, and foot process effacement, plays a central role in the development of DN in both type 1 and type 2 diabetes. 4,[9][10][11] Despite the crucial importance of the kidney, both as therapeutic target and as determinant of the prognosis of patients with DN, little is known about the mechanisms underlying kidney damage associated with diabetes.…”

“…12,[24][25][26] Importantly, postmitotic podocytes exhibit high levels of basal autophagy as a key regulator of podocyte and glomerular maintenance. 13 Additionally, a strong body of evidence supports the role for maintenance of endothelial function in diabetes to limit DN progression involving homeostasis of multiple systems 7,[27][28][29][30] such as NOS3/eNOS (nitric oxide synthase 3 [endothelial cell]) activity, 31 glycocalyx production, 32,33 EDN/endothelin actions [34][35][36][37][38] and balanced VEGF (vascular endothelial growth factor) 33,39,40 and ANGPT/angiopoietin systems. 41 Endothelial cells may also use autophagy as a coping mechanism to metabolic stress.…”