The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.

Astrocyte–endothelial interactions at the blood–brain barrier

Acute renal failure (ARF), classically defined as an abrupt decrease in kidney function that leads to accumulation of nitrogenous wastes such as blood urea nitrogen and creatinine, is a common clinical problem with increasing incidence, serious consequences, unsatisfactory therapeutic options, and

/pdf/update-on-mechanisms-of-ischemic-acute-kidney-injury-1ype1s84nf.pdf

Update on mechanisms of ischemic acute kidney injury.

Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia or nephrotoxicity. An underlying feature is a rapid decline in GFR usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or CKD patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future.

/pdf/pathophysiology-of-acute-kidney-injury-57ami3f8ia.pdf

Pathophysiology of Acute Kidney Injury

Maintenance of blood volume, vascular tone, and hemodynamic stability depends on a set of elegant interactions between the heart and kidney. For some time, physicians have recognized that severe dysfunction in either of these organs seldom occurs in isolation. However, only recently have we attempted to define and apply the widespread concept of the cardiorenal syndrome (CRS). Despite our growing use of the term, there is still some debate as to its true definition. More important, the process itself remains enigmatic; our understanding of the complex physiological, biochemical, and hormonal derangements that encompass the CRS is woefully deficient and may lead to improper medical management of patients.

Because renal dysfunction portends such a dismal prognosis in cardiac failure and vice versa, there has been a recent surge of interest in identifying precise pathophysiological connections between the failing heart and kidneys. Understanding the mechanisms involved in the CRS will allow us to target therapies that interrupt this dangerous feedback cycle.

In 2004, a working group of investigators at the National Heart, Lung, and Blood Institute defined the CRS as a state in which therapy to relieve heart failure (HF) symptoms is limited by further worsening renal function.1 Although this definition is succinct and understandable and probably reflects the most common use of the term, some authors argue that it is simplistic to the point of being inaccurate.2 Several groups have recently proposed that the definition of CRS be broadened in an attempt to stress the complex and bidirectional nature of pathophysiological interactions between the failing heart and kidneys. That is, each dysfunctional organ has the ability to initiate and perpetuate disease in the other organ through common hemodynamic, neurohormonal, and immunologic/biochemical feedback pathways.

Proper use of the term CRS should correct a common misunderstanding: that kidney dysfunction in HF …

Cardiorenal syndrome: new perspectives.

In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. This article provides an overview of key aspects of mitochondrial biology in endothelial cells, including subcellular location, biogenesis, dynamics, autophagy, reactive oxygen species production and signaling, calcium homeostasis, regulated cell death, and heme biosynthesis. In each section, we introduce key concepts and then review studies showing the importance of that mechanism to endothelial control of vasomotor tone, angiogenesis, and/or inflammatory activation. We particularly highlight the small number of clinical and translational studies that have investigated each mechanism in human subjects. Finally, we review interventions that target different aspects of mitochondrial function and their effects on endothelial function. The ultimate goal of such research is the identification of new approaches for therapy. The reviewed studies make it clear that mitochondria are important in endothelial physiology and pathophysiology. A great deal of work will be needed, however, before mitochondria-directed therapies are available for the prevention and treatment of cardiovascular disease.

Mitochondria and Endothelial Function

Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotectivein both in vitro and in vivo models ofischaemic acute renal failure Methods. Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25–400 IU/ml) in the presence of hypoxia (1% O2), normoxia (21% O2) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia–reperfusion (IR) injury. Results. In the in vitro model, hypoxia (1% O2) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5±0.5% vs 25 IU/ml EPO 1.8±0.4% vs 200 IU/ml EPO 0.9±0.2%, n = 9, P<0.05). At high concentrations (400 IU/ml), EPO also stimulated thymidine incorporation in cells exposed to hypoxia with or without subsequent normoxia. LDH release was not significantly affected. In the unilateral IR model, EPO pre-treatment significantly attenuated outer medullary thick ascending limb (TAL) apoptosis (EPO 2.2±1.0% of cells vs vehicle 6.5±2.2%, P<0.05, n = 5) and potentiated mitosis (EPO 1.1±0.3% vs vehicle 0.5±0.3%, respectively, P<0.05) within 24 h. EPO-treated rats exhibited enhanced PCNA staining within the proximal straight tubule (6.9±0.7% vs vehicle 2.4±0.5% vs sham 0.3±0.2%, P<0.05), proximal convoluted tubule (2.3±0.6% vs vehicle 1.1±0.3% vs sham 1.2±0.3%, P<0.05) and TAL (4.7±0.9% vs vehicle 0.6±0.3% vs sham 0.3±0.2%, P<0.05). The frequency of tubular profiles with luminal cast material was also reduced (32.0±1.6 vs vehicle 37.0±1.3%, P = 0.05). EPO-treated rats subjected to bilateral IR injury exhibited similar histological improvements to the unilateral IR injury model, as well as significantly lower peak plasma creatinine concentrations than their vehicle-treated controls (0.04±0.01 vs 0.21±0.08 mmol/l, respectively, P<0.05). EPO had no effect on renal function in sham-operated controls. Conclusions. The results suggest that, in addition to its well-known erythropoietic effects, EPO inhibits apoptotic cell death, enhances tubular epithelial regeneration and promotes renal functional recovery in hypoxic or ischaemic acute renal injury.

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Erythropoietin protects against ischaemic acute renal injury

Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure.

https://www.kidney-international.org/article/S0085-2538(15)50538-3/pdf

Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants

For the past decade, an attempt has been made by many research groups to define the roles of the growing number of Bcl-2 gene family proteins in the apoptotic process. The Bcl-2 family consists of pro-apoptotic (or cell death) and anti-apoptotic (or cell survival) genes and it is the balance in expression between these gene lineages that may determine the death or survival of a cell. The majority of studies have analysed the role/s of the Bcl-2 genes in cancer development. Equally important is their role in normal tissue development, homeostasis and non-cancer disease states. Bcl-2 is crucial for normal development in the kidney, with a deficiency in Bcl-2 producing such malformation that renal failure and death result. As a corollary, its role in renal disease states in the adult has been sought. Ischaemia is one of the most common causes of both acute and chronic renal failure. The section of the kidney that is most susceptible to ischaemic damage is the outer zone of the outer medulla. Within this zone the proximal tubules are most sensitive and often die by necrosis or desquamate. In the distal nephron, apoptosis is the more common form of cell death. Recent results from our laboratory have indicated that ischaemia-induced acute renal failure is associated with up-regulation of two anti-apoptotic Bcl-2 proteins (Bcl-2 and Bcl-XL) in the damaged distal tubule and occasional up-regulation of Bax in the proximal tubule. The distal tubule is a known reservoir for several growth factors important to renal growth and repair, such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). One of the likely possibilities for the anti-cell death action of the Bcl-2 genes is that the protected distal cells may be able to produce growth factors that have a further reparative or protective role via an autocrine mechanism in the distal segment and a paracrine mechanism in the proximal cells. Both EGF and IGF-1 are also up-regulated in the surviving distal tubules and are detected in the surviving proximal tubules, where these growth factors are not usually synthesized. As a result, we have been using in vitro methods to test: (i) the relative sensitivities of renal distal and proximal epithelial cell populations to injury caused by mechanisms known to act in ischaemia-reperfusion; (ii) whether a Bcl-2 anti-apoptotic mechanism acts in these cells; and (iii) whether an autocrine and/or paracrine growth factor mechanism is initiated. The following review discusses the background to these studies as well as some of our preliminary results.

Betty Pat

Papers

Erythropoietin protects against ischaemic acute renal injury

Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure.

Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants

Bcl-2 genes and growth factors in the pathology of ischaemic acute renal failure.

Bcl-2 in endothelial cells is increased by vitamin E and α-lipoic acid supplementation but not exercise training