Renal endothelial dysfunction in diabetic nephropathy

Abstract

Endothelial dysfunction has been posited to play an important role in the pathogenesis of diabetic nephropathy (DN). Due to the heterogeneity of endothelial cells (ECs), it is difficult to generalize about endothelial responses to diabetic stimuli. At present, there are limited techniques fordirectly measuring EC function in vivo, so diagnosis of endothelial disorders still largely depends on indirect assessment of mediators arising from EC injury. In the kidney microcirculation, both afferent and efferent arteries, arterioles and glomerular endothelial cells (GEnC) have all been implicated as targets of diabetic injury. Both hyperglycemia per se, as well as the metabolic consequences of glucose dysregulation, are thought to lead to endothelial cell dysfunction. In this regard, endothelial nitric oxide synthase (eNOS) plays a central role in EC dysfunction. Impaired eNOS activity can occur at numerous levels, including enzyme uncoupling, post-translational modifications, internalization and decreased expression. Reduced nitric oxide (NO) bioavailability exacerbates oxidative stress, further promoting endothelial dysfunction and injury. The injured ECs may then function as active signal transducers of metabolic, hemodynamic and inflammatory factors that modify the function and morphology of the vessel wall and interact with adjacent cells, which may activate a cascade of inflammatory and proliferative and profibrotic responses in progressive DN. Both pharmacological approaches and potential regenerative therapies hold promise for restoration of impaired endothelial cells in diabetic nephropathy.

Fig. (1). Pathogenesis of Renal EC dysfunction during DN

Hyperglycemia, along with its metabolites and other stimuli, activates various signaling pathways and induces numerous growth factors, cytokines, ROS generation and eNOS impairment, leading to renal EC dysfunction. Injured ECs may further contribute to the progression of DN in turn. RAS: renin-angiotensin System; GFs: growth factors; eNOS: endothelial Nitric Oxide; AGE: advanced glycation end products; RAGE: the receptor of AGE; ROS: reactive oxygen species; GFR: glomerular filtration rate.

Fig. (2). Interaction of renal ECs with adjacent cells

A. In glomeruli, GEnCs are surrounded by the interdigitated foot process from podocytes. Glomerular mesangial cells (glomerular pericytes) are located in the area between GEnCs. The injured endothelium serves as an active signal transducer for metabolic, hemodynamic and inflammatory factors that modify the function and morphology of the vessel wall and interacts with adjacent cells. Growth factors involved in this crosstalk include VEGF:Vascular endothelial growth factor; Ang: Angiopoietins and PDGF: Platelet-derived growth factor. B. Pericytes are embedded within the vascular basement membrane of blood microvessels. Circulating and renal resident inflammatory/immune cells, pericytes and renal ECs interact each other, influence to effect tissue repair/fibrosis processes. Pro-inflammatory, pro-fibrotic and adhesive cytokines, metalloproteinases, and growth factors mediate this communication.VCAM-1: Vascular cell adhesion molecule-1, ILs: interleukins, MMPs: Matrix metalloproteinases. PTX: proximal tubular cell, HGF: hepatic growth factor.