Workshop: Endothelial Cell Dysfunction Leading to Diabetic Nephropathy

Abstract

Abstract-Clinical manifestations of diabetic nephropathy are an expression of diabetic microangiopathy. This review revisits the previously proposed Steno hypothesis and advances our hypothesis that development of endothelial cell dysfunction represents a common pathophysiological pathway of diabetic complications. Specifically, the ability of glucose to scavenge nitric oxide is proposed as the initiation phase of endothelial dysfunction. Gradual accumulation of advanced glycated end products and induction of plasminogen activator inhibitor-1, resulting in the decreased expression of endothelial nitric oxide synthase and reduced generation of nitric oxide, are proposed to be pathophysiologically critical for the maintenance phase of endothelial dysfunction. The proposed conceptual shift toward the role of endothelial dysfunction in diabetic complications may provide new strategies for their prevention. Key Words: nitric oxide synthase Ⅲ collagen Ⅲ plasminogen Ⅲ diabetes mellitus T ype 2 diabetes mellitus has reached epidemic proportions, and one of its ominous complications, diabetic nephropathy, represents today the leading cause of end-stage renal failure. 1,2 Clinical manifestations of diabetic nephropathy include microalbuminuria, heralding incipient nephropathy, followed by albuminuria or nephrotic-range proteinuria, elevated blood pressure, development of glomerulosclerosis, tubulointerstitial fibrosis, and relentless decline in glomerular filtration rate. [1][2][3][4] The most characteristic prognostic feature in this group of patients is the high risk of cardiovascular complications, much more so than in diabetics without nephropathy. Several important mediators of diabetic nephropathy have been proposed, such as transforming growth factor-␤, accumulation of the extracellular matrix, reactive oxygen intermediates, and protein kinase C, to name a few, and have been comprehensively reviewed. [1][2][3][4] However, the pathophysiological origin of clinical presentations of diabetic nephropathy can be traced back to microvasculopathy and macrovasculopathy (Figure 1), and the focus of this review will be on the mechanisms for development and maintenance of endothelial cell dysfunction in diabetic nephropathy.In 1988, Torsten Deckert delivered a Claude Bernard Lecture in which the Steno hypothesis, a unifying proposal that albuminuria of diabetic nephropathy is a sign of the global vascular dysfunction, was introduced. 5 Because only less than one third of patients with type I diabetes mellitus tend to develop renal disease, it was speculated that a genetic predisposition, supposedly at the level of N-deacetylase (a key enzyme responsible for the sulfation of heparan sulfate proteoglycans) gene polymorphism, contributes to the loss of the anionic charge barrier of endothelial cells and basement membranes, resulting in a widespread rise in vascular permeability and vasculopathy. The hypothesis to be developed below takes stock of the above broad view that albuminuria is an indicator of a systemic microvascular l...

Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan

“…[63][64][65][66][67][68][69][70][71] The protein leakage in diabetic hypertensive patients has been attributed to endothelial dysfunction, which is present in both diabetes and hypertension. 72 Microalbuminuria in type II diabetic, 73 or nondiabetic hypertensive 74 patients has been associated, besides renal failure, with cardiovascular complications. The latter study 74 showed that for every 10-fold increase in the urinary albumin-creatinine ratio, the composite end point (death, MI or stroke) was increased by 57%, cardiovascular mortality by 97.7%, all cause mortality by 75.2%, stroke by 51% and MI by 45%.…”

Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits

“…Chronic vascular adaptations could contribute to the preservation of renal function during acute exercise and confer renoprotective effects in diseases where endothelial function is compromised. This effect could be clinically relevant because renal pathophysiological processes resulting from hypercholesterolemia (49) as well as diabetic (13) and hypertensive (55) nephropathies have been associated with dysfunction of the renal vascular endothelium.…”

“…EDHF seems to be essentially involved in the local regulation of blood flow in small resistance vessels (10,37), with the exception of the coronary and renal vascular beds where it also contributes to the modulation of vascular reactivity in conduit arteries (3). Endothelium dysfunction, which can be evidenced by an impairment in endothelium-dependent relaxation, plays a pivotal role in the pathogenesis of cardiovascular diseases, such as arterial hypertension and coronary heart disease (54), as well as in diabetic angiopathy (13). Moreover, NO interferes with key events involved in the development of atherosclerosis, such as smooth muscle cell proliferation, platelet adhesion and vessel wall interaction, and monocyte and leucocyte adhesion (54).…”

“…On the other hand, few studies have focused on the chronic effects of exercise on the visceral circulation, such as the kidney, where blood flow is known to be reduced during acute exercise (1,9). However, it is noteworthy that the kidneys, which play a pivotal role in whole body homeostasis, undergo dramatic changes in their blood flow patterns during exercise (12) and are involved in the course of disease states such as primary arterial hypertension (20) and diabetes (13).…”

Association of HLA Class I and II Antigens with Vitiligo in Egyptian Population

“…Endothelial dysfunction is associated with decreased NO availability, either through loss of NO production or through loss of NO biological activity [60]. NO production is diminished in cells which are subject to oxidative stress.…”