Abstract
The endothelium constitutes the inner lining of the vessels and is a cornerstone of vascular homeostasis. Besides their classical barrier function, the endothelial cells are notably involved in the regulation of vasomotor tone, the control of tissue inflammation and of thrombosis. Within the renal microvasculature, the endothelium is characterized by a remarkable structural heterogeneity, related to the different and highly specialized functions of endothelial cells, from the preglomerular arterioles to the peritubular capillary bed. The kidneys receive as much as 1 l/min of blood in the adult, and the microvasculature plays a key role in renal physiology. As a consequence, persistent endothelial alterations in arterioles, glomerular capillaries, vasa rectae and/or peritubular capillaries are susceptible to impair the function of the organ, and to contribute to the development of both acute and chronic kidney disease. Although the recognition of systemic endothelial dysfunction related to chronic kidney disease has led to significant research interest over the last decades, less is known about the role of endothelial alterations within the kidney. The study of the renal endothelium is particularly difficult, both in experimental models and in humans. Nonetheless, important technical advances have been made, especially regarding the development of intravital microscopy for imaging of the kidney microvascularization and transgenic tissue-specific knockouts in mice. Accumulating evidence now provides exciting insights on the pathophysiological role of renal endothelial dysfunction in the initiation and the progression of kidney disease. In this issue of Cardiovascular and Hematological Disorders – Drug Targets, 3 complementary articles review and discuss evolving concepts in the field of renal endothelial dysfunction. First, renal endothelial dysfunction plays an important role in several frequent aetiologies of acute kidney injury. In particular, damage of the endothelium due to ischemia-reperfusion is a major contributor to the allograft injury occurring immediately after transplantation, and to subsequent persistent lesions. In this issue, Basile and Yoder summarize how various alterations in endothelial function and structure may sequentially contribute to the pathogenesis of kidney injury. They discuss important therapeutic perspectives directed to the protection of the endothelium during the early phase and the repair phase of acute kidney injury. Furthermore, in hyperglycemic conditions, endothelial cells are particularly vulnerable. Interestingly, systemic and renal endothelial dysfunctions are found in diabetic patients with normal urine albumin excretion and glomerular filtration rate, suggesting that endothelial injury precedes overt nephropathy. Here, Cheng and Harris present a thorough review of the current evidence supporting a deleterious role of renal endothelial injury in the pathogenesis of diabetic nephropathy. They discuss the possibility that the altered endothelium may act as an active signal transducer for metabolic, hemodynamic and inflammatory factors that modify the function and morphology of the vessel wall and of glomeruli. A particular focus on modifications of the cross-talk between the injured endothelium and adjacent cells suggests that important indirect mechanisms also contribute to the consequences of endothelial alterations in the progression of kidney diseases. Finally, Abed and collegues provide an overview of the expanding domain of connexins in renal endothelial physiology and pathophysiology. Connexins are transmembrane proteins which form intercellular gap junctions. Gap-junctional communication is essential in the coordination and integration of microvascular function by the endothelial cells. Several connexins have been found to be expressed in the kidney, either in the vasculature or in the tubular epithelium. Due to their ability to regulate physiological and pathological signals in the endothelium, connexins draw a growing interest among the actors involved in renal endothelial dysfunction. Although challenging, the modulation of connexin expression, especially that of Cx37, Cx40 and Cx43, may be of value in settings where the endothelial injury plays an important role, as is the case in crescentic glomerulonephritis, kidney ischemia-reperfusion or antibody-mediated allograft rejection. Since current evidence supports the importance of endothelial alterations in the progression of renal damage, the prevention of renal endothelial injury emerges as a promising treatment strategy in kidney diseases. Depending on the clinical setting, a reduction of renal endothelial dysfunction is susceptible to alleviate inflammation, hemodynamic disturbances, hypoxia and extracellular matrix synthesis. As suggested by the accumulating evidence presented in the review articles of this issue, therapeutic strategies may target distinct and complementary aspects of endothelial pathophysiology, thereby reducing specific consequences of renal endothelial functional alterations. Future research directions in this exciting field may include specifically targeted delivery of drugs based on endothelial alterations, preservation of endothelium-derived hyperpolarizing factors, pharmacological maintenance of endothelial NO-synthase activation in altered shear stress conditions, and silencing of endothelial proinflammatory genes.
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