Cardiovascular & Haematological Disorders - Drug Targets - Volume 14, Issue 1, 2014

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.

Acute kidney injury is associated with alterations in vascular tone that contribute to an overall reduction in GFR. Studies in animal models indicate that ischemia triggers alterations in endothelial function that contribute significantly to the overall degree and severity of a kidney injury. Putative mediators of vasoconstriction that may contribute to the initial loss of renal blood flow and GFR are highlighted. In addition, there is discussion of how intrinsic damage to the endothelium impairs homeostatic responses in vascular tone as well as promotes leukocyte adhesion and exacerbating the reduction in renal blood flow. The timing of potential therapies in animal models as they relate to the evolution of AKI, as well as the limitations of such approaches in the clinical setting are discussed. Finally, we discuss how acute kidney injury induces permanent alterations in renal vascular structure. We posit that the cause of the sustained impairment in kidney capillary density results from impaired endothelial growth responses and suggest that this limitation is a primary contributing feature underlying progression of chronic kidney disease.

The renal endothelium plays a critical role in kidney physiopathology as it is implicated in various processes such as the regulation of vasomotor tone, the control of tissue inflammation and thrombosis. Recent evidence highlights direct implication of renal endothelial dysfunction in the progression of chronic kidney disease. Renal endothelial dysfunction is a multifaceted process in which chemokines, cytokines, prothrombotic factors and adhesion molecules are known to play a crucial role. Apart from paracrine cell-to-cell signaling, the role for gap junction-mediated intercellular communication in renal physiopathology has been recently suggested. Gap junction channels are formed by the hexameric assembly of connexins and directly connect the cytoplasm of adjacent cells. Due to their ability to regulate multiple physiological and pathological signals connexins are currently taking an important place in the list of actors involved in renal endothelial function and dysfunction. In this review we will focus on possible implications of connexins in the physiopathological processes associated with renal vascular endothelium.

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.

Vitamin D plays an essential role in calcium homeostasis and bone metabolism, but recent research has exposed a larger spectrum of biological actions that also includes induction of cell proliferation, immunomodulation, and control of other hormonal systems. Many cells that play an important role in the cardiovascular system express the Vitamin D receptor (VDR) and respond to 1,25-(OH)2D (the active product of vitamin D conversion by hydroxylase) with cell-specific function and gene regulation. These cells include cardiomyocytes, vascular endothelial cells, vascular smooth muscle cells, phagocytes, and cells of the nephron, which produce renin. VDR activators (calcitriol and paricalcitol) are available for the treatment of vitamin D deficiency, which can result from inadequate cutaneous production and/or low dietary intake. Vitamin-D deficient patients present a higher risk of cardiovascular disease than the general population. Recent clinical observations have shown that VDR activator therapy provides survival benefit and also has a positive impact on cardiovascular function. Compelling results have arisen from previous studies of mice with disrupted genes of the vitamin D signaling pathways. In mice lacking VDR or CYP27B1 (1α-hydroxylase – an enzyme, which converts vitamin D to its active form), in addition to the expected phenotype (hypocalcaemia, secondary hyperparathyroidism and osteomalacia), development of hypertension and cardiac hypertrophy were also observed. Moreover, these mice presented with overexpression of renin and atrial natriuretic peptide. VDR may play a role in regulating smooth-muscle-cell (SMC) proliferation, thrombosis, fibrinolysis and vessel relaxation. The influence of VDR activators on the modulation of renin expression and vascular function may reduce mortality, organ damage, and cardiovascular morbidity in VDR-activator-treated patients with hypertension. Since clinical use of calcitriol is largely limited, because of the side effect of hypercalcemia, calcitriol analogues have been synthesized to obtain compounds with better therapeutic profiles. The main purpose of this article is to review the role of vitamin D and vitamin D receptor activators in cardiovascular diseases, especially hypertension and its treatment. Due to the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D supplementation therapy may be warranted in this population.

Stroke is the most feared complication of atrial fibrillation but for over fifty years there has been no simple, effective preventative alternative to warfarin. The development of new risk algorithms such as CHADSVASC has resulted in more patients being recommended anticoagulation therapy. Fixed dose oral anticoagulation is a landmark in drug development for atrial fibrillation. The differences between the drugs are discussed and the trial data examined. As we enter this new frontier of therapy, there is no doubt that these drugs will transform the delivery of anticoagulation for patients with atrial fibrillation.

Dietary recommendations are key to cardiovascular disease (CVD) management. The underpinning evidence is generally based on data generated from single nutrient or food types. However, food is not consumed in such a manner, and components may interact synergistically or antagonistically depending on the dietary composition. Analyses of dietary patterns have attempted to address these important issues. The aim of this review is to present the current evidence on three major dietary patterns and their relationship with CVD. The most widely reported is the Mediterranean diet, which is characterised by abundant use of olive oil, and plant-based foods, moderate consumption of fish, dairy products, alcohol with meals, and a relatively low intake of red meat. The strongest evidence of causality has been established for the Mediterranean diet and unlike other dietary patterns has been shown to significantly reduce major CVD events. The Dietary Approach to Stop Hypertension (DASH), emphasising fruit, vegetables and low fat dairy products, has successfully been shown to lower blood pressure and cholesterol levels. However, its true effects on CVD under freeliving conditions have yet to be fully explored. The available evidence is encouraging for CVD prevention, but long-term effectiveness is unclear. Very low-carbohydrate diets appear to exert their favourable effect on CVD risk factors via weight loss. However, longterm effectiveness and safety remains unclear. The available evidence supports the role of the DASH and Mediterranean diets in the prevention of CVD.

Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are effective and safe oral incretin-based antihyperglycemic drugs. In preclinical studies, DPP-4 inhibitors have demonstrated cardiovascular benefits, independent of glycemic control, in patients with type-2 diabetes mellitus. Since 2005, various DPP-4 inhibitors (sitagliptin, linagliptin and saxagliptin) have been clinically available in the United States. Since 2013, alogliptin is the 4th approved DPP-4 inhibitor available on the market. Studies have shown that alogliptinis non-inferior to comparator drugs among newly diagnosed type 2 diabetes mellitus patients. Alogliptin can effectively be used as a single agent or as an add-on drug in combination with other glucose lowering drugs with favorable outcomes on glycemic control and HbA1C levels.

Myocardial Ischemia/Reperfusion (I/R) induced injury has widespread detrimental effects partially negating the benefits obtained from early revascularization in Acute Myocardial Infarction. Various complex mechanisms contribute to I/R injury and different agents targeting those specific mechanisms are being studied. Despite continued research and widespread interest, none of them have become incorporated into everyday practice. The TRPV1 (transient receptor potential vanilloid 1) channel is a non selective cation channel predominantly expressed in sensory neurons with the nerve fibers innervating the heart and blood vessels. Multiple studies have demonstrated the importance of the activation of TRPV1 and subsequent release of sensory neurotransmitters in cardioprotection. This review focuses on the role of TRPV1 in prevention of cardiac I/R injury, the work that has been done so far and future implications for TRPV1 agonists as cardioprotective agents.

Warfarin has remained the mainstay of stroke prevention in atrial fibrillation for the past 60 years. Recently, two new groups of novel oral anticoagulants- direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) have shown promising results in well conducted clinical trials in terms of efficacy, safety and convenience of usage. However, in real world practice these novel agents come with their share of side effects and drawbacks which the prescribing physician must be aware about. In this review we discuss the role of these novel agents in real world clinical practice – their advantages, disadvantages and future directions.