Endothelial dysfunction in diabetic nephropathy: state of the art and potential significance for non-diabetic renal disease
Coen D. A. Stehouwer
VU University Medical Center, Amsterdam, The Netherlands
Correspondence and offprint requests to: Coen D. A. Stehouwer, Professor of Medicine, VU University Medical Center, 1081 HV Amsterdam, The Netherlands. Email: cda.stehouwer{at}vumc.nl
Keywords: diabetes; endothelial dysfunction; microalbuminuria; renal disease
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An epidemic of diabetic nephropathy and cardiovascular disease
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Much of the disease burden in diabetes occurs in patients with diabetic nephropathy, as they have the highest chance of developing cardiovascular disease as well as severe retinopathy and neuropathy [1]. Two issues appear crucial in stemming the epidemic of diabetic nephropathy and cardiovascular disease. One is the prevention of diabetes and the solution here from a public health point of view lies in the prevention of obesity. The other is improved understanding of the pathogenesis of renal and vascular disease in diabetes. Here, endothelial dysfunction (ED) is thought to play a key role. What is the state of the art with regard to this hypothesis?
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Endothelial dysfunction: the concept
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The endothelium is an important site of control of vascular functions [2]. Vascular endothelium normally decreases vascular tone; limits leukocyte adhesion and, thus, inflammatory activity in the vessel wall; regulates vascular permeability to nutrients, macromolecules and leukocytes; inhibits platelet adhesion and aggregation by producing prostacyclin, nitric oxide (NO) and ectonucleotidases; limits activation of the coagulation cascade by the thrombomodulinprotein C, heparan sulphateantithrombin and tissue factortissue factor pathway inhibitor interactions; and regulates fibrinolysis by producing t-PA and its inhibitor, PAI-1. NO is a particularly important endothelium-derived mediator, because of its vasodilator, anti-platelet, anti-proliferative, anti-adhesive, permeability-decreasing and anti-inflammatory properties.
ED can be considered present when endothelial properties have changed in a way that is inappropriate with regard to the preservation of organ function. For example, basement membrane synthesis may be altered, which can contribute to arterial stiffening and increased microvascular permeability; vascular tone and permeability may increase, which contributes to increased blood pressure and atherogenesis; and the endothelium may lose its antithrombotic and profibrinolytic properties and may instead acquire prothrombotic and antifibrinolytic properties. Such alterations (endothelial dysfunctions) do not necessarily occur simultaneously and may differ according to the nature of the injury and the intrinsic properties of the endothelium (e.g. venous vs arterial vs microvascular). Endothelial activation designates one specific type of ED characterized by (usually, inflammatory cytokine-induced) increased interactions with blood leukocytes, in which adhesion molecules and chemoattractants are essential.
ED can be conceptualized as a transducer of atherogenic risk factors and is thought to play an important role both in the initiation and the progression of atherosclerosis. In this view, risk factors, such as oxidatively modified low-density lipoprotein cholesterol, smoking, hypertension, angiotensin-II and diabetes, initiate atherosclerosis through endothelial activation. The predilection to atherosclerosis of arterial branching points, bifurcations and convexities is explained by the fact that blood flow there is non-laminar or even turbulent and shear stress low or oscillatory, and that these conditions increase endothelial activation, effects that are enhanced by hypertension. These risk factors also have in common that NO availability is decreased through decreased production and (or) increased degradation, which furthers endothelial activation.
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Endothelial dysfunction: ready for clinical use?
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Much of the above is based on experimental data. Testing these concepts in patients, above all, requires reliable measurements of endothelial function. Endothelial function cannot be measured directly in humans and, thus, indirect estimates are often used, which include endothelium-dependent vasodilation (EDV) and plasma levels of endothelium-derived regulatory mediators, such as NOx, endothelin, von Willebrand factor, soluble thrombomodulin, soluble adhesion molecules, t-PA and PAI-1. But are these tests valid estimates of ED? On the one hand, many cross-sectional studies have shown impaired EDV and high levels of endothelium-derived regulatory proteins in diseases that involve injury to the endothelium, such as atherothrombosis, pre-eclampsia and vasculitis, as well as in individuals with risk factors for atherothrombosis. Moreover, prospective studies have shown that individuals with impaired EDV and high levels of endothelium-derived regulatory proteins have an adverse cardiovascular prognosis [36]. On the other hand, the interpretation of these tests is not as straightforward as one would wish. Firstly, tests intended to estimate NO-mediated EDV in part measure effects of other endothelial vasodilators, such as prostacyclin and endothelium-derived hyperpolarizing factor. This has two consequences, which are not often emphasized, namely (a) that quantitatively normal EDV does not guarantee normal endothelial function, as (for example) less NO might be compensated by more endothelium-derived hyperpolarizing factor, and (b) that abnormal EDV in the presence of normal sodium nitroprusside-mediated vasodilation (i.e. normal vascular smooth muscle cell responsiveness to exogenous NO) does not guarantee impaired endothelial function, as this combination of findings is also compatible with an abnormal smooth muscle cell response to endothelium-derived vasodilators other than NO. Secondly, the concept that high plasma levels of endothelium-derived mediators reflect ED in clinically relevant arteries (such as the coronary and carotid) requires (i) that other cell types are not an important source, (ii) that synthesis is more important than clearance and (iii) that endothelial function in the microvasculature parallels that in large arteries, because microvascular endothelium, with its very large surface area and synthetic capacity, is the most important determinant of plasma levels of endothelium-derived mediators. Information on the validity of these assumptions is scarce. In some cases, the assumptions are clearly invalid. For example, PAI-1 can be produced not only by endothelial cells, but also by hepatocytes, adipocytes and vascular smooth muscle cells.
Clinical use of the concept of ED faces three major problems. Firstly, the estimates that exist for assessing endothelial function in vivo in humans are reasonable but far from perfect. Secondly, there is a lack of markers for specific endothelial functions, such as large artery permeability. Thirdly, specific interventions to improve endothelial function are not available. Statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, oestrogen, L-arginine, antioxidants and folic acid have all been shown to improve some aspects of endothelial function, but these compounds have many other effects, so that it has not been possible to determine to what extent improvement of endothelial function explains clinical effects (e.g. statin-induced reduction of risk of myocardial infarction).
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Does endothelial dysfunction cause (micro)albuminuria?
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(Micro)albuminuria in type 1 and 2 diabetes is usually [7], but perhaps not always [8,9], accompanied by generalized ED: there is impairment of many aspects of endothelial function in many vascular beds. This association between microalbuminuria and ED is also seen in non-diabetic individuals [1013]. In fact, ED precedes and predicts the onset of microalbuminuria [6,11,1315]. It is, therefore, tempting to postulate that ED in (micro)albuminuria explains why (micro)albuminuria is a consistent marker of increased risk of atherothrombosis [16,17]. This raises the question of how ED could cause (micro)albuminuria. Alternatively, the link between ED and microalbuminuria could be explained by a common antecedent which causes both, but the association between ED and microalbuminuria remains when adjusted for e.g. common risk factors. Theoretically, ED could cause albuminuria both directly, by increasing glomerular pressure and glomerular basement membrane permeability, and indirectly, by influencing mesangial cell and podocyte function in a paracrine fashion (e.g. through inflammatory mechanisms). Importantly, the molecular pathways by which ED causes (micro)albuminuria have yet to be worked out.
Diabetes is a state of chronic, low-grade inflammation [4,18]. Causes of inflammation in diabetes strongly resemble those of ED and include hyperglycaemia, advanced glycation endproducts, adipokines (e.g. tumour necrosis factor-
), dyslipidaemia and hypertension. Regardless of the presence of diabetes, chronic, low-grade inflammation is associated with the occurrence and progression of (micro)albuminuria [6,13] and with risk of atherothrombotic disease [6,13,19]. In addition, chronic, low-grade inflammation can be both cause and consequence of ED [2,6,18,20] and the two are tightly linked. Figure 1 shows how conventional risk factors, ED and inflammation may interact to cause cardiovascular disease in diabetes.
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When does endothelial dysfunction occur in diabetes?
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In type 1 diabetes, ED precedes and may cause diabetic microangiopathy, but it is not clear whether hyperglycaemia is a sufficient cause of ED [2126]. In my view, it is more likely that hyperglycaemia predisposes to the development of ED and that other factors, genetic or environmental, play a role in determining who among type 1 diabetic patients goes on to develop ED, nephropathy and aggressive angiopathy and who does not.
In type 2 diabetes, ED is present from the onset of the disease and is strongly related to adverse outcomes [4,13]. Type 2 diabetes mostly occurs in the setting of the metabolic syndrome, but ED in type 2 diabetes is not explained by hypertension, obesity or dyslipidaemia [27]. It is not clear whether this diabetes-specific ED is caused by hyperglycaemia or other factors. An important potential determinant is increased inflammatory activity (Figure 1). In addition, part of the ED in type 2 diabetes may be primary, i.e. cause of diabetes rather than caused by diabetes (see below).
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Can endothelial dysfunction cause type 2 diabetes?
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According to a novel concept [28], ED in large arteries, an early and prominent event in atherothrombosis, is paralleled by ED in resistance vessels and metabolically important capillary beds that contributes to the development of hypertension and insulin resistance (and, later, type 2 diabetes). How can ED impair insulin-induced glucose disposal? In an endothelium-dependent process termed capillary recruitment, insulin can redirect blood flow in skeletal muscle from non-nutritive capillaries (those that are not coupled to muscle cells) to nutritive capillaries (those that are) and, thus, increase glucose disposal even without increasing total blood flow [2931]. In this way, physical integrity and normal function of the arteriolar and capillary endothelium are prerequisites for normal metabolic insulin action. Indeed, ED can cause insulin resistance both when the microvascular endothelium is otherwise healthy but cannot react properly to insulin (endothelial insulin resistance) and when the microvascular endothelium is injured through other mechanisms, such as age-related capillary drop-out (rarefaction, i.e. reduced capillary density per volume of tissue). More generally, microvascular rarefaction and ED may provide a common pathway through which common risk factors, such as age, obesity, smoking and low birth weight, increase the risk of developing insulin resistance, hypertension and renal disease in diabetic and non-diabetic individuals [3235] (Figure 2). Clearly, this hypothesis is far from proven, but it focuses attention on microvascular function as a potential treatment target [35,36].

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Fig. 2. Microvascular dysfunction as a potential link between common risk factors on the one hand and insulin resistance, hypertension and renal disease on the other.
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Conclusions
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The endothelium is an important locus of control of vascular functions; reasonable but not perfect methods exist for assessing ED in vivo in humans.
ED in diabetes complicated by (micro)albuminuria is generalized. The close link between (micro)albuminuria and ED is an attractive but unproven explanation for the fact that microalbuminuria is a risk marker for atherothrombosis. ED predicts the occurrence of microalbuminuria, but whether this is causal has not been determined.
ED in diabetes is caused by hyperglycaemia, advanced glycation endproducts and the components of the metabolic syndrome. It is not clear whether hyperglycaemia is sufficient to cause ED. In type 2 diabetes, ED occurs from the onset of the disease and is strongly related to adverse outcomes.
Microvascular ED is closely associated with and may contribute to insulin resistance, hypertension and renal disease, regardless of the presence of diabetes. If this hypothesis is correct, then improvement of microvascular function should be considered an important target of treatment.
Conflict of interest statement. None declared.
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