Physiology and pathophysiology of Na+/H+ exchange and Na+-K+-2Cl(-) cotransport in the heart, brain, and blood
ABSTRACT Maintenance of a stable cell volume and intracellular pH is critical for normal cell function. Arguably, two of the most important ion transporters involved in these processes are the Na+/H+ exchanger isoform 1 (NHE1) and Na+ -K+ -2Cl- cotransporter isoform 1 (NKCC1). Both NHE1 and NKCC1 are stimulated by cell shrinkage and by numerous other stimuli, including a wide range of hormones and growth factors, and for NHE1, intracellular acidification. Both transporters can be important regulators of cell volume, yet their activity also, directly or indirectly, affects the intracellular concentrations of Na+, Ca2+, Cl-, K+, and H+. Conversely, when either transporter responds to a stimulus other than cell shrinkage and when the driving force is directed to promote Na+ entry, one consequence may be cell swelling. Thus stimulation of NHE1 and/or NKCC1 by a deviation from homeostasis of a given parameter may regulate that parameter at the expense of compromising others, a coupling that may contribute to irreversible cell damage in a number of pathophysiological conditions. This review addresses the roles of NHE1 and NKCC1 in the cellular responses to physiological and pathophysiological stress. The aim is to provide a comprehensive overview of the mechanisms and consequences of stress-induced stimulation of these transporters with focus on the heart, brain, and blood. The physiological stressors reviewed are metabolic/exercise stress, osmotic stress, and mechanical stress, conditions in which NHE1 and NKCC1 play important physiological roles. With respect to pathophysiology, the focus is on ischemia and severe hypoxia where the roles of NHE1 and NKCC1 have been widely studied yet remain controversial and incompletely elucidated.
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- "To decipher how the pHe-gradients in chronic wounds might arise, we studied the expression levels of essential pHe-regulatory ion transporters in punch biopsies from human wounds (Additional file 1: Table S2). We assessed the protein expression level of Na+/H+-exchanger-1 (NHE1), a ubiquitously expressed transporter which is highly regulated (e.g. by cytokines, H2O2, reduced intracellular pH) 41, 42, and which contributes importantly to the development of acidic pHe, e.g. in carcinomas 41, 43, 44. Immunofluorescence analysis of NHE1 in sections from intact skin, wound peripheries and centers (Fig. 4A,B,Additional File 1: Fig. S8) revealed an increase in total and plasma membrane NHE1-density at wound peripheries, yet not at the central wound region, when compared with surrounding intact tissue. "
ABSTRACT: Wound repair is a quiescent mechanism to restore barriers in multicellular organisms upon injury. In chronic wounds, however, this program prematurely stalls. It is known that patterns of extracellular signals within the wound fluid are crucial to healing. Extracellular pH (pHe) is precisely regulated and potentially important in signaling within wounds due to its diverse cellular effects. Additionally, sufficient oxygenation is a prerequisite for cell proliferation and protein synthesis during tissue repair. It was, however, impossible to study these parameters in vivo due to the lack of imaging tools. Here, we present luminescent biocompatible sensor foils for dual imaging of pHe and oxygenation in vivo. To visualize pHe and oxygen, we used time-domain dual lifetime referencing (tdDLR) and luminescence lifetime imaging (LLI), respectively. With these dual sensors, we discovered centripetally increasing pHe-gradients on human chronic wound surfaces. In a therapeutic approach, we identify pHe-gradients as pivotal governors of cell proliferation and migration, and show that these pHe-gradients disrupt epidermal barrier repair, thus wound closure. Parallel oxygen imaging also revealed marked hypoxia, albeit with no correlating oxygen partial pressure (pO2)-gradient. This highlights the distinct role of pHe-gradients in perturbed healing. We also found that pHe-gradients on chronic wounds of humans are predominantly generated via centrifugally increasing pHe-regulatory Na+/H+-exchanger-1 (NHE1)-expression. We show that the modification of pHe on chronic wound surfaces poses a promising strategy to improve healing. The study has broad implications for cell science where spatial pHe-variations play key roles, e.g. in tumor growth. Furthermore, the novel dual sensors presented herein can be used to visualize pHe and oxygenation in various biomedical fields.Theranostics 04/2014; 4(7):721-735. DOI:10.7150/thno.9052 · 8.02 Impact Factor
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- "Thus far, it is not clear how the change in cytoplasmic pH induces basal autophagy in neurons. Because intracellular pH is affected by cellular energy production/consumption and metabolic stresses , and metabolic changes are key regulators of autophagy , it is possible that NHE-induced regulation of autophagy is mediated by a signaling mechanism similar to the regulatory mechanism of energy deprivation-induced autophagy. It is also possible that another novel regulatory mechanism is involved in NHE-induced autophagy, because NHEs affect basal levels of autophagy, which is often regarded as one regulated under a mechanism different from energy deprivation-induced autophagy . "
ABSTRACT: In polyglutamine diseases, an abnormally elongated polyglutamine results in protein misfolding and accumulation of intracellular aggregates. Autophagy is a major cellular degradative pathway responsible for eliminating unnecessary proteins, including polyglutamine aggregates. Basal autophagy constitutively occurs at low levels in cells for the performance of homeostatic function, but the regulatory mechanism for basal autophagy remains elusive. Here we show that the Na(+)/H(+) exchanger (NHE) family of ion transporters affect autophagy in a neuron-like cell line (Neuro-2a cells). We showed that expression of NHE1 and NHE5 is correlated to polyglutamine accumulation levels in a cellular model of Huntington's disease, a fatal neurodegenerative disorder characterized by accumulation of polyglutamine-containing aggregate formation in the brain. Furthermore, we showed that loss of NHE5 results in increased polyglutamine accumulation in an animal model of Huntington's disease. Our data suggest that cellular pH regulation by NHE1 and NHE5 plays a role in regulating basal autophagy and thereby promotes autophagy-mediated degradation of proteins including polyglutamine aggregates.PLoS ONE 11/2013; 8(11):e81313. DOI:10.1371/journal.pone.0081313 · 3.23 Impact Factor
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- "NKCC1 and the NHEs are known to be present on neurons and astrocytes within the brain parenchyma. If inhibitors of these transporters reach the parenchyma, they will produce marked reductions in the responses of the parenchymal cells to ischaemia with less cellular uptake of Na+ and Cl−, less release of K+, reduced cell swelling [12, 36, 56, 71, 81, 82] and presumably also less contraction of the interstitial spaces. These inhibitor effects within the parenchyma may have consequences quite independently of any direct effects of the inhibitors on the endothelial cells that counter changes in the rates of blood–brain barrier secretion and ISF loss to CSF seen without the inhibitors (see e.g. "
ABSTRACT: Ions and water transported across the endothelium lining the blood-brain barrier contribute to the fluid secreted into the brain and are important in maintaining appropriate volume and ionic composition of brain interstitial fluid. Changes in this secretion process may occur after stroke. The present study identifies at transcript and protein level ion transporters involved in the movement of key ions and examines how levels of certain of these alter following oxidative stress. Immunohistochemistry provides evidence for Cl(-)/HCO3 (-) exchanger, AE2, and Na(+), HCO3 (-) cotransporters, NBCe1 and NBCn1, on brain microvessels. mRNA analysis by RT-PCR reveals expression of these transporters in cultured rat brain microvascular endothelial cells (both primary and immortalized GPNT cells) and also Na(+)/H(+) exchangers, NHE1 (primary and immortalized) and NHE2 (primary cells only). Knock-down using siRNA in immortalized GPNT cells identifies AE2 as responsible for much of the Cl(-)/HCO3 (-) exchange following extracellular chloride removal and NHE1 as the transporter that accounts for most of the Na(+)/H(+) exchange following intracellular acidification. Transcript levels of both AE2 and NHE1 are increased following hypoxia/reoxygenation. Further work is now required to determine the localization of the bicarbonate transporters to luminal or abluminal membranes of the endothelial cells as well as to identify and localize additional transport mechanisms that must exist for K(+) and Cl(-).Pflügers Archiv - European Journal of Physiology 09/2013; 466(5). DOI:10.1007/s00424-013-1342-9 · 4.10 Impact Factor