What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium?

Abstract

Microalbuminuria is an important risk factor for cardiovascular disease and progressive renal impairment. This holds true in the general population and particularly in those with diabetes, in whom it is common and marks out those likely to develop macrovascular disease and progressive renal impairment. Understanding the pathophysiological mechanisms through which microalbuminuria occurs holds the key to designing therapies to arrest its development and prevent these later manifestations. Microalbuminuria arises from the increased passage of albumin through the glomerular filtration barrier. This requires ultrastructural changes rather than alterations in glomerular pressure or filtration rate alone. Compromise of selective glomerular permeability can be confirmed in early diabetic nephropathy but does not correlate well with reported glomerular structural changes. The loss of systemic endothelial glycocalyx--a protein-rich surface layer on the endothelium--in diabetes suggests that damage to this layer represents this missing link. The epidemiology of microalbuminuria reveals a close association with systemic endothelial dysfunction and with vascular disease, also implicating glomerular endothelial dysfunction in microalbuminuria. Our understanding of the metabolic and hormonal sequelae of hyperglycaemia is increasing, and we consider these in the context of damage to the glomerular filtration barrier. Reactive oxygen species, inflammatory cytokines and growth factors are key players in this respect. Taken together with the above observations and the presence of generalised endothelial dysfunction, these considerations lead to the conclusion that glomerular endothelial dysfunction, and in particular damage to its glycocalyx, represents the most likely initiating step in diabetic microalbuminuria.

Fig. 1

The relationship between hyperglycaemia, insulin resistance, endothelial dysfunction, macrovascular disease and microalbuminuria in type 1 and type 2 diabetes. Proposed major pathways are represented by red arrows; those of less certain significance by black arrows. The diagram illustrates, for the example, a possible mechanism for the increased risk of microalbuminuria in patients with type 1 diabetes and a susceptibility to insulin resistance. Particularly in type 2 diabetes, other pathways, not directly involving endothelial dysfunction, are likely in the pathogenesis of macrovascular disease and may also contribute to microalbuminuria (broken arrows)

Fig. 2

Representation of a cross-section through the GFB showing the three-layer structure consisting of glomerular endothelium and glycocalyx, glomerular basement membrane (GBM) and podocyte foot processes. Albumin, represented by orange ellipses, does not pass through the normal GFB in significant amounts

Fig. 3

Pathways to microalbuminuria in diabetes. Hyperglycaemia, through increased mitochondrial superoxide production, dysregulates key intracellular metabolic pathways. These in turn lead to the production of effectors that directly cause glomerular endothelial cell (GEnC) dysfunction (particularly of the glycocalyx) and disturb podocyte–endothelial cell communication. This results in microalbuminuria. Progression of these lesions and development of other glomerular changes, including podocyte damage, lead to overt diabetic nephropathy

Fig. 4

Proposed mechanism of glomerular filtration barrier damage leading to diabetic microalbuminuria. High glucose causes dysregulation of mediators including TNFα and enhanced production of ROS, which directly damage the glomerular endothelial glycocalyx leading to microalbuminuria. Increased levels of pro-angiogenic molecules, including VEGF and inflammatory mediators, induce an activated and more permeable glomerular endothelial cell phenotype