Experimental physiology
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Experimental physiology · Nov 2012
ReviewNovel targets for sepsis-induced kidney injury: the glomerular arterioles and the sympathetic nervous system.
Sepsis and septic shock are the most common causes of acute kidney injury (AKI) in the intensive care unit, and mortality remains high despite improvements in our ability to support vital organs. The lack of development of effective treatments is partly because there has been little advance in our understanding of the pathophysiology of septic AKI, owing to the difficulty in conducting experiments on critically ill patients and use of inappropriate experimental models. Recently, however, a number of new concepts have emerged that challenge existing dogma and give insights into the causes of AKI. ⋯ New evidence also indicates that the increased sympathetic nerve activity that occurs in sepsis may contribute to the induction of organ failure. Experimental studies indicate that inhibition of central sympathetic outflow with α(2)-adrenoceptor agonists or treatment with β(1)-adrenoceptor antagonists might reduce mortality in experimental endotoxaemia and sepsis. The possibility that these beneficial actions are partly dependent on a reduction in the excessive cytokine release caused by marked and prolonged sympathetic activation is discussed.
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Experimental physiology · Feb 2009
ReviewCongenital nephrogenic diabetes insipidus: what can we learn from mouse models?
Aquaporins (AQPs) are central players in mammalian physiology, allowing efficient water transport through cellular membranes. To date, 13 different aquaporins have been identified in mammals (AQP0-AQP12). Knocking out genes in mice and identification of mutations in the human genes provided important information on the role of AQPs in normal physiology. ⋯ In humans, mutations in the AQP2 gene cause congenital nephrogenic diabetes insipidus (NDI), a disorder characterized by an inability to concentrate urine in response to vasopressin. Until the recent development of several congenital NDI mouse models, our knowledge on AQP2 regulation was primarily based on in vitro studies. This review focuses on the similarities between the in vitro and in vivo studies and discusses new insights into congenital NDI obtained from the mouse models.
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Experimental physiology · May 2008
ReviewThe discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice.
During several months of 2002, severe acute respiratory syndrome (SARS) caused by SARS-coronavirus (SARS-CoV) spread rapidly from China throughout the world, causing more than 800 deaths due to the development of acute respiratory distress syndrome (ARDS), which is the severe form of acute lung injury (ALI). Interestingly, a novel homologue of angiotensin-converting enzyme, termed angiotensin-converting enzyme 2 (ACE2), has been identified as a receptor for SARS-CoV. Angiotensin-converting enzyme and ACE2 share homology in their catalytic domain and provide different key functions in the renin-angiotensin system (RAS). ⋯ Importantly, our recent studies using ACE2 knockout mice have demonstrated that ACE2 protects murine lungs from ARDS. Furthermore, SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo, which can be attenuated by blocking the renin-angiotensin pathway, suggesting that the activation of the pulmonary RAS influences the pathogenesis of ALI/ARDS and SARS.
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Experimental physiology · Mar 2007
ReviewGlucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms?
A fuller understanding of the central mechanisms involved in controlling food intake and metabolism is likely to be crucial for developing treatments to combat the growing problem of obesity in Westernised societies. Within the hypothalamus, specialized neurones respond to both appetite-regulating hormones and circulating metabolites to regulate feeding behaviour accordingly. Thus, the activity of hypothalamic glucose-excited and glucose-inhibited neurones is increased or decreased, respectively, by an increase in local glucose concentration. ⋯ Whilst the intracellular signalling mechanisms through which glucose-sensing neurones detect changes in the concentration of the sugar have been investigated quite extensively, many elements remain poorly understood. Furthermore, the similarities, or otherwise, with other nutrient-sensing cells, including pancreatic islet cells, are not completely resolved. In this review, we discuss recent advances in this field and explore the potential involvement of AMP-activated protein kinase and other nutrient-regulated protein kinases.
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Oxidative stress plays an important role in the pathophysiology of vascular diseases. Reactive oxygen species, especially superoxide anion and hydrogen peroxide, are important signalling molecules in cardiovascular cells. Enhanced superoxide production increases nitric oxide inactivation and leads to an accumulation of peroxynitrites and hydrogen peroxide. ⋯ Potential sources of vascular superoxide production include NADPH-dependent oxidases, xanthine oxidases, lipoxygenases, mitochondrial oxidases and nitric oxide synthases. Studies performed during the last decade have shown that NADPH oxidase is the most important source of superoxide anion in phagocytic and vascular cells. Evidence from experimental animal and human studies suggests a significant role of NADPH oxidase activation in the vascular remodelling and endothelial dysfunction found in cardiovascular diseases.