Non-voltage gated Ca2+ channel signaling in glomerular cells in kidney health and disease.

Positioned at the head of the nephron, the renal corpuscle generates a plasma ultrafiltrate to initiate urine formation. Three major cell types within the renal corpuscle, the glomerular mesangial cells, podocytes, and glomerular capillary endothelial cells communicate via endocrine and paracrine signaling mechanisms to maintain structure and function of the glomerular capillary network and filtration barrier. Ca2+ signaling mediated by several distinct plasma membrane Ca2+ channels modulates the functions of all three cell types. The last two decades have witnessed pivotal advances in understanding of Ca2+ channel function and regulation in glomerular cells, particularly non-voltage gated Ca2+ channels, in health and renal disease. This review summarizes the current knowledge of the physiological and pathological impact of non-voltage gated Ca2+ channel signaling in glomerular capillary endothelium, mesangial cells and podocytes. The main focus is on transient receptor potential and store-operated Ca2+ channels, but ionotropic N-methyl-D-aspartate receptors and purinergic 2X receptors also are discussed. This update of Ca2+ channel functions in the renal corpuscle and their cellular signaling cascades is intended to inform development of therapeutic strategies targeting these channels to treat kidney diseases, particularly diabetic nephropathy.

Mechanisms underlying the health benefits of intermittent hypoxia conditioning.

Intermittent hypoxia (IH) is commonly associated with pathological conditions, particularly obstructive sleep apnoea. However, IH is also increasingly used to enhance health and performance and is emerging as a potent non-pharmacological intervention against numerous diseases. Whether IH is detrimental or beneficial for health is largely determined by the intensity, duration, number and frequency of the hypoxic exposures and by the specific responses they engender. Adaptive responses to hypoxia protect from future hypoxic or ischaemic insults, improve cellular resilience and functions, and boost mental and physical performance. The cellular and systemic mechanisms producing these benefits are highly complex, and the failure of different components can shift long-term adaptation to maladaptation and the development of pathologies. Rather than discussing in detail the well-characterized individual responses and adaptations to IH, we here aim to summarize and integrate hypoxia-activated mechanisms into a holistic picture of the body's adaptive responses to hypoxia and specifically IH, and demonstrate how these mechanisms might be mobilized for their health benefits while minimizing the risks of hypoxia exposure.

Molecular Mechanisms of High-Altitude Acclimatization.

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.

Inhibition of interleukin-6 on matrix protein production by glomerular mesangial cells and the pathway involved.

Activation of immunological pathways and disturbances of extracellular matrix (ECM) dynamics are important contributors to the pathogenesis of chronic kidney diseases. Glomerular mesangial cells (MCs) are critical for homeostasis of glomerular ECM dynamics. Interleukin-6 (IL-6) can act as a pro/anti-inflammatory agent relative to cell types and conditions. This study investigated whether IL-6 influences ECM protein production by MCs and the regulatory pathways involved. Experiments were carried out in cultured human MCs (HMCs) and in mice. We found that overexpression of IL-6 and its receptor decreased the abundance of fibronectin and collagen type IV in MCs. ELISA and immunoblot analysis demonstrated that thapsigargin [an activator of store-operated Ca2+ entry (SOCE)], but not the endoplasmic reticulum stress inducer tunicamycin, significantly increased IL-6 content. This thapsigargin effect was abolished by GSK-7975A, a selective inhibitor of SOCE, and by silencing Orai1 (the channel protein mediating SOCE). Furthermore, inhibition of NF-κB pharmacologically and genetically significantly reduced SOCE-induced IL-6 production. Thapsigargin also stimulated nuclear translocation of the p65 subunit of NF-κB. Moreover, MCs overexpressing IL-6 and its receptor in HMCs increased the content of the glucagon-like peptide-1 receptor (GLP-1R), and IL-6 inhibition of fibronectin was attenuated by the GLP-1R antagonist exendin 9-39. In agreement with the HMC data, specific knockdown of Orai1 in MCs using the targeted nanoparticle delivery system in mice significantly reduced glomerular GLP-1R levels. Taken together, our results suggest a novel SOCE/NF-κB/IL-6/GLP-1R signaling pathway that inhibits ECM protein production by MCs.

Ischaemic and hypoxic conditioning: potential for protection of vital organs.

NEW FINDINGS: What is the topic of this review? Remote ischaemic preconditioning (RIPC) and hypoxic preconditioning as novel therapeutic approaches for cardiac and neuroprotection. What advances does it highlight? There is improved understanding of mechanisms and signalling pathways associated with ischaemic and hypoxic preconditioning, and potential pitfalls with application of these therapies to clinical trials have been identified. Novel adaptations of preconditioning paradigms have also been developed, including intermittent hypoxia training, RIPC training and RIPC-exercise, extending their utility to chronic settings. ABSTRACT: Myocardial infarction and stroke remain leading causes of death worldwide, despite extensive resources directed towards developing effective treatments. In this Symposium Report we highlight the potential applications of intermittent ischaemic and hypoxic conditioning protocols to combat the deleterious consequences of heart and brain ischaemia. Insights into mechanisms underlying the protective effects of intermittent hypoxia training are discussed, including the activation of hypoxia-inducible factor-1 and Nrf2 transcription factors, synthesis of antioxidant and ATP-generating enzymes, and a shift in microglia from pro- to anti-inflammatory phenotypes. Although there is little argument regarding the efficacy of remote ischaemic preconditioning (RIPC) in pre-clinical models, this strategy has not consistently translated into the clinical arena. This lack of translation may be related to the patient populations targeted thus far, and the anaesthetic regimen used in two of the major RIPC clinical trials. Additionally, we do not fully understand the mechanism through which RIPC protects the vital organs, and co-morbidities (e.g. hypercholesterolemia, diabetes) may interfere with its efficacy. Finally, novel adaptations have been made to extend RIPC to more chronic settings. One adaptation is RIPC-exercise (RIPC-X), an innovative paradigm that applies cyclical RIPC to blood flow restriction exercise (BFRE). Recent findings suggest that this novel exercise modality attenuates the exaggerated haemodynamic responses that may limit the use of conventional BFRE in some clinical settings. Collectively, intermittent ischaemic and hypoxic conditioning paradigms remain an exciting frontier for the protection against ischaemic injuries.

Cardioprotection by intermittent hypoxia conditioning: evidence, mechanisms, and therapeutic potential.

The calibrated application of limited-duration, cyclic, moderately intense hypoxia-reoxygenation increases cardiac resistance to ischemia-reperfusion stress. These intermittent hypoxic conditioning (IHC) programs consistently produce striking reductions in myocardial infarction and ventricular tachyarrhythmias after coronary artery occlusion and reperfusion and, in many cases, improve contractile function and coronary blood flow. These IHC protocols are fundamentally different from those used to simulate sleep apnea, a recognized cardiovascular risk factor. In clinical studies, IHC improved exercise capacity and decreased arrhythmias in patients with coronary artery or pulmonary disease and produced robust, persistent, antihypertensive effects in patients with essential hypertension. The protection afforded by IHC develops gradually and depends on ß-adrenergic, δ-opioidergic, and reactive oxygen-nitrogen signaling pathways that use protein kinases and adaptive transcription factors. In summary, adaptation to intermittent hypoxia offers a practical, largely unrecognized means of protecting myocardium from impending ischemia. The myocardial and perhaps broader systemic protection provided by IHC clearly merits further evaluation as a discrete intervention and as a potential complement to conventional pharmaceutical and surgical interventions.

Intermittent hypoxia training blunts cerebrocortical presenilin 1 overexpression and amyloid-ß accumulation in ethanol-withdrawn rats.

Abrupt cessation of chronic alcohol consumption triggers signaling cascades that harm vulnerable brain regions and produce neurobehavioral deficits. We have demonstrated that a program of intermittent, normobaric hypoxia training (IHT) in rats prevents brain damage and neurobehavioral impairment resulting from abrupt ethanol withdrawal (EW). Moreover, EW induced expression of stress-activated protein kinase p38 and presenilin 1 (PS1), the catalytic subunit of γ-secretase that produces the neurotoxic amyloid-ß (Aß) peptides Aß40 and Aß42. We tested the hypotheses that 1) IHT limits EW-induced activation of the p38-PS1 axis, thereby attenuating γ-secretase activation and Aß accumulation, and 2) EW disables heat shock protein 25 (HSP25), a p38 substrate, molecular chaperone, and antioxidant, and provokes protein carbonylation in a manner suppressed by IHT. Adult male rats completed two cycles of a 4-wk ethanol diet (6.5% wt/vol) and a 3-wk EW or an isocaloric, dextrin-based control diet. A 20-day IHT program (5-8 daily cycles of 5-10 min of 9.5-10% fractional inspired O2 + 4 min of 21% fractional inspired O2) was administered during the first EW phase. After the second EW phase, the brain was excised and the prefrontal cortex extracted. PS1, phosphorylated p38 (p-p38), and HSP25 were analyzed by immunoblot, PS1 messenger RNA by quantitative polymerase chain reaction, protein carbonyl content by spectrometry, and Aß40 and Aß42 contents by enzyme-linked immunosorbent assay. IHT attenuated the EW-associated increases in PS1, p-p38, Aß40, Aß42, and protein carbonyl contents, but not that of PS1 messenger RNA, while preserving functionally competent HSP25 dimers in EW rats. Collectively, these findings suggest that IHT may attenuate EW-induced γ-secretase overactivation by suppressing activation of the p38-PS1 axis and by preventing oxidative protein damage.

δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium.

Intermittent, normobaric hypoxia confers robust cardioprotection against ischemia-induced myocardial infarction and lethal ventricular arrhythmias. δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) have been implicated in cardioprotective phenomena, but their roles in intermittent hypoxia are unknown. This study examined the contributions of DOR and ROS in mediating intermittent hypoxia-induced cardioprotection. Mongrel dogs completed a 20 day program consisting of 5-8 daily, 5-10 min cycles of moderate, normobaric hypoxia (FIO2 0.095-0.10), with intervening 4 min room air exposures. Subsets of dogs received the DOR antagonist naltrindole (200 µg/kg, sc) or antioxidant N-acetylcysteine (250 mg/kg, po) before each hypoxia session. Twenty-four hours after the last session, the left anterior descending coronary artery was occluded for 60 min and then reperfused for 5 h. Arrhythmias detected by electrocardiography were scored according to the Lambeth II conventions. Left ventricles were sectioned and stained with 2,3,5-triphenyl-tetrazolium-chloride, and infarct sizes were expressed as percentages of the area at risk (IS/AAR). Intermittent hypoxia sharply decreased IS/AAR from 41 ± 5 % (n = 12) to 1.8 ± 0.9 % (n = 9; P < 0.001) and arrhythmia score from 4.1 ± 0.3 to 0.7 ± 0.2 (P < 0.001) vs. non-hypoxic controls. Naltrindole (n = 6) abrogated the cardioprotection with IS/AAR 35 ± 5 % and arrhythmia score 3.7 ± 0.7 (P < 0.001 vs. untreated intermittent hypoxia). N-acetylcysteine (n = 6) interfered to a similar degree, with IS/AAR 42 ± 3 % and arrhythmia score 4.7 ± 0.3 (P < 0.001 vs. untreated intermittent hypoxia). Without the intervening reoxygenations, hypoxia (n = 4) was not cardioprotective (IS/AAR 50 ± 8 %; arrhythmia score 4.5 ± 0.5; P < 0.001 vs. intermittent hypoxia). Thus DOR, ROS and cyclic reoxygenation were obligatory participants in the gradually evolving cardioprotection produced by intermittent hypoxia.

Impact of Age on Cognitive Testing Practice Effects and Cardiorespiratory Responses.

Objective: This study tested the hypothesis that healthy aging attenuates cognitive practice effects and, consequently, limits the familiarity-associated reductions in heart rate (HR) and breathing frequency (BF) responses during retesting. Methods: Twenty-one cognitively normal older and younger adults (65 ± 2 vs. 26 ± 1 years old) participated in the study. Mini-Mental State Examination (MMSE), Digit-Span-Test (DST), Trail Making Test (TMT-B), and California Verbal Learning Test (CVLT-II) were administered twice at 3-week intervals, while HR and BF were monitored by electrocardiography and plethysmography, respectively. Results: Cognitive performances were not affected by the age factor, and the retest factor only affected CVLT-II. HR and BF increased only in the younger adults (p < .01) during cognitive tests; retesting attenuated these responses (retest factor p < .01). Long-delay free-recall in CVLT-II was unchanged in cognitively normal older versus younger adults. Healthy aging did not diminish short-term memory assessed by DST and CVLT-II short-delay or long-delay free-recalls. Conclusions: Only CVLT-II, but not MMSE, DST or TMT-B, demonstrated cognitive retesting practice effects in the younger and older adults. Cognitive testing at 3-week intervals in cognitively normal older and younger subjects revealed divergent cardiorespiratory responses to MMSE, DST, and TMT-B cognitive testing, particularly HR, which increased only in younger adults and to a lesser extent during retesting despite the absence of practice effects.

Store-operated Ca2+ channel signaling: Novel mechanism for podocyte injury in kidney disease.

Studies over the last decade have markedly broadened our understanding of store-operated Ca2+ channels (SOCs) and their roles in kidney diseases and podocyte dysfunction. Podocytes are terminally differentiated glomerular visceral epithelial cells which are tightly attached to the glomerular capillary basement membrane. Podocytes and their unique foot processes (pedicels) constitute the outer layer of the glomerular filtration membrane and the final barrier preventing filtration of albumin and other plasma proteins. Diabetic nephropathy and other renal diseases are associated with podocyte injury and proteinuria. Recent evidence demonstrates a pivotal role of store-operated Ca2+ entry (SOCE) in maintaining structural and functional integrity of podocytes. This article reviews the current knowledge of SOCE and its contributions to podocyte physiology. Recent studies of the contributions of SOC dysfunction to podocyte injury in both cell culture and animal models are discussed, including work in our laboratory. Several downstream signaling pathways mediating SOC function in podocytes also are examined. Understanding the pivotal roles of SOC in podocyte health and disease is essential, as SOCE-activated signaling pathways are potential treatment targets for podocyte injury-related kidney diseases.

Mechanisms maintaining cerebral perfusion during systemic hypotension are impaired in elderly adults.

Postural hypotension abruptly lowers cerebral perfusion, producing unsteadiness which worsens with aging. This study addressed the hypothesis that maintenance of cerebral perfusion weakens in the elderly due to less effective cerebrovascular autoregulation and systemic cardiovascular responses to hypotension. In healthy elderly (n = 13, 68 ± 1 years) and young (n = 13, 26 ± 1 years) adults, systemic hypotension was induced by rapid deflation of bilateral thigh cuffs after 3-min suprasystolic occlusion, while heart rate (HR), mean arterial pressure (MAP), and blood flow velocity of the middle cerebral artery (VMCA) were recorded. VMCA/MAP indexed cerebrovascular conductance (CVC). Durations and rates of recovery of MAP and VMCA from their respective postdeflation nadirs were compared between the groups. Thigh-cuff deflation elicited similar hypotension and cerebral hypoperfusion in the elderly and young adults. However, the time elapsed (TΔ) from cuff deflation to the nadirs of MAP and VMCA, and the time for full recovery (TR) from nadirs to baselines were significantly prolonged in the elderly subjects. The response rates of HR (ΔHR, i.e. cardiac factor), MAP (ΔMAP, i.e. vasomotor factor), and CVC following cuff deflation were significantly slower in the elderly. Collectively, the response rates of the cardiac, vasomotor, and CVC factors largely explained TRVMCA. However, the TRVMCA/ΔMAP slope (-3.0 ± 0.9) was steeper (P = 0.046) than the TRVMCA/ΔHR slope (-1.1 ± 0.4). The TRVMCA/ΔCVC slope (-2.4 ± 0.6) was greater (P = 0.072) than the TRVMCA/ΔHR slope, but did not differ from the TRVMCA/ΔMAP slope (P = 0.52). Both cerebrovascular autoregulatory and systemic mechanisms contributed to cerebral perfusion recovery during systemic hypotension, and the vasomotor factor was predominant over the cardiac factor. Recovery from cerebral hypoperfusion was slower in the elderly adults because of the age-diminished rates of the CVC response and cardiovascular reflex regulation. Systemic vasoconstriction predominated over increased HR for restoring cerebral perfusion after abrupt onset of systemic hypotension.

Habitual physical activity improves vagal cardiac modulation and carotid baroreflex function in elderly women.

The impact of habitual physical activity on vagal-cardiac function and baroreflex sensitivity in elderly women is poorly characterized. This study compared vagal-cardiac modulation and carotid baroreflex (CBR) function in eight physically active (67.6 ± 1.9 years; peak O2 uptake 29.1 ± 2.5 mL/min/kg) versus eight sedentary (67.3 ± 1.8 years; peak O2 uptake 18.6 ± 0.9 mL/min/kg) elderly women. Heart rate (HR) variabilities and maximal changes of HR and mean arterial pressure (MAP) elicited by 5-s pressure pulses between +40 and -80 mmHg applied to the carotid sinus were measured at rest and during carotid baroreceptor unloading effected by -15 mmHg lower-body negative pressure (LBNP). HR variability was greater in active than sedentary women in both low (0.998 ± 0.286 versus 0.255 ± 0.063 bpm2; P = 0.036) and high (0.895 ± 0.301 versus 0.156 ± 0.045 bpm2; P = 0.044) frequency domains. CBR-HR gains (bpm/mmHg) were greater (fitness factor P < 0.001) in active versus sedentary women at rest (-0.146 ± 0.014 versus -0.088 ± 0.011) and during LBNP (-0.105 ± 0.014 versus -0.065 ± 0.008). CBR-MAP gains (mmHg/mmHg) tended to be greater (fitness factor P = 0.077) in active versus sedentary women at rest (-0.132 ± 0.013 versus -0.110 ± 0.011) and during LBNP (-0.129 ± 0.015 versus -0.113 ± 0.013). However, LBNP did not potentiate CBR-MAP gains in either sedentary or active women (LBNP factor P = 0.94), and it depressed CBR-HR gains in both groups (LBNP factor P = 0.003). CBR-HR gains in the sedentary women did not differ (sex factor P = 0.65) from gains reported in age-matched sedentary men, although CBR-MAP gains tended to be greater (sex factor P = 0.109) in the men. Thus, tonic vagal modulation indicated by HR variability and dynamic vagal responses assessed by CBR-HR gain were augmented in physically active women. Enhanced vagal-cardiac function may protect against senescence-associated cardiac electrical and hemodynamic instability in elderly women.

Pyruvate protects the brain against ischemia-reperfusion injury by activating the erythropoietin signaling pathway.

BACKGROUND AND PURPOSE: Pyruvate is known to be cytoprotective through antioxidant and anti-inflammatory mechanisms. We tested the hypothesis that pyruvate protects the brain against ischemia-reperfusion injury by inducing endogenous erythropoietin (EPO) expression. METHODS: Pyruvate's protective effect was evaluated in C6 glioma cells and HT22 neuronal cells subjected to transient oxygen glucose deprivation. Cell viability (calcein AM assay) and expression of hypoxia-inducible factor-1α, EPO, Akt and Erk (immunoblot), and EPO receptor (reverse transcription-polymerase chain reaction) were analyzed. Transient focal cerebral ischemia in rats was induced by 2 hours middle cerebral artery occlusion followed by 24 hours reperfusion. Pyruvate or saline was infused from 60 minutes occlusion until 30 minutes reperfusion. Lesion volume and DNA fragmentation were assessed by 2,3,5-triphenyltetrazolium staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, respectively. Immunoblots were conducted to determine cerebral EPO contents. RESULTS: Pyruvate increased cell viability, hypoxia-inducible factor-1α, EPO, and Akt phosphorylation. Small interfering RNA suppression of hypoxia-inducible factor-1α and EPO abolished pyruvate-induced cytoprotection. In the rat stroke model, pyruvate reduced lesion volume by 84% and DNA fragmentation by 77% versus controls; increased EPO content paralleled these cerebroprotective actions of pyruvate. CONCLUSIONS: Pyruvate activation of the hypoxia-inducible factor-1α-EPO signaling cascade in neurons and glia could protect the brain from ischemia-reperfusion injury.

Adaptive Responses to Hypoxia and/or Hyperoxia in Humans.

Significance: Oxygen is indispensable for aerobic life, but its utilization exposes cells and tissues to oxidative stress; thus, tight regulation of cellular, tissue, and systemic oxygen concentrations is crucial. Here, we review the current understanding of how the human organism (mal-)adapts to low (hypoxia) and high (hyperoxia) oxygen levels and how these adaptations may be harnessed as therapeutic or performance enhancing strategies at the systemic level. Recent Advances: Hyperbaric oxygen therapy is already a cornerstone of modern medicine, and the application of mild hypoxia, that is, hypoxia conditioning (HC), to strengthen the resilience of organs or the whole body to severe hypoxic insults is an important preparation for high-altitude sojourns or to protect the cardiovascular system from hypoxic/ischemic damage. Many other applications of adaptations to hypo- and/or hyperoxia are only just emerging. HC-sometimes in combination with hyperoxic interventions-is gaining traction for the treatment of chronic diseases, including numerous neurological disorders, and for performance enhancement. Critical Issues: The dose- and intensity-dependent effects of varying oxygen concentrations render hypoxia- and/or hyperoxia-based interventions potentially highly beneficial, yet hazardous, although the risks versus benefits are as yet ill-defined. Future Directions: The field of low and high oxygen conditioning is expanding rapidly, and novel applications are increasingly recognized, for example, the modulation of aging processes, mood disorders, or metabolic diseases. To advance hypoxia/hyperoxia conditioning to clinical applications, more research on the effects of the intensity, duration, and frequency of altered oxygen concentrations, as well as on individual vulnerabilities to such interventions, is paramount. Antioxid. Redox Signal. 37, 887-912.

Hypoxic breathing produces more intense hypoxemia in elderly women than in elderly men.

Background: Brief hypoxic exposures are increasingly applied as interventions for aging-related conditions. To optimize the therapeutic impact of hypoxia, knowledge of the sex-related differences in physiological responses to hypoxia is essential. This study compared hypoxia-induced hypoxemic responses in elderly men and women. Methods: Seven elderly men (70.3 ± 6.0 years old) and nine women (69.4 ± 5.5 years old) breathed 10% O2 for 5 min while arterial (SaO2; transcutaneous photoplethysmography) and cerebral tissue O2 saturation (ScO2; near-infrared spectroscopy), ventilatory frequency, tidal volume, minute-ventilation, and partial pressures of end-tidal O2 (PETO2) and CO2 (mass spectrometry) were continuously monitored. Cerebral tissue oxygen extraction fraction (OEF) equaled (SaO2-ScO2)/SaO2. Results: During 5 min hypoxia SaO2 fell from 97.0 ± 0.8% to 80.6 ± 4.6% in the men and from 96.3 ± 1.4% to 72.6 ± 4.0% in the women. The slope ΔSaO2/min was steeper in the women than the men (-4.71 ± 0.96 vs. -3.24 ± 0.76%/min; p = 0.005). Although SaO2 fell twice as sharply per unit decrease in PETO2 in the women than the men (-1.13 ± 0.11 vs. -0.54 ± 0.06%/mmHg; p = 0.003), minute-ventilation per unit hypoxemia increased less appreciably in the women (-0.092 ± 0.014 vs. -0.160 ± 0.021 L/min/%; p = 0.023). OEF fell with hypoxia duration in the women, but remained stable in the men. Conclusion: During 5 min hypoxic breathing, elderly women experience more intense hypoxemia and reduced chemoreflex sensitivity vs. their male counterparts, which may lower OEF stability in women despite augmented O2 dissociation from hemoglobin during hypoxia. These sex-related differences merit attention when implementing brief hypoxic exposures for therapeutic purposes.

Hypoxia and brain aging: Neurodegeneration or neuroprotection?

The absolute reliance of the mammalian brain on oxygen to generate ATP renders it acutely vulnerable to hypoxia, whether at high altitude or in clinical settings of anemia or pulmonary disease. Hypoxia is pivotal to the pathogeneses of myriad neurological disorders, including Alzheimer's, Parkinson's and other age-related neurodegenerative diseases. Conversely, reduced environmental oxygen, e.g. sojourns or residing at high altitudes, may impart favorable effects on aging and mortality. Moreover, controlled hypoxia exposure may represent a treatment strategy for age-related neurological disorders. This review discusses evidence of hypoxia's beneficial vs. detrimental impacts on the aging brain and the molecular mechanisms that mediate these divergent effects. It draws upon an extensive literature search on the effects of hypoxia/altitude on brain aging, and detailed analysis of all identified studies directly comparing brain responses to hypoxia in young vs. aged humans or rodents. Special attention is directed toward the risks vs. benefits of hypoxia exposure to the elderly, and potential therapeutic applications of hypoxia for neurodegenerative diseases. Finally, important questions for future research are discussed.

Impact of High Altitude on Cardiovascular Health: Current Perspectives.

Globally, about 400 million people reside at terrestrial altitudes above 1500 m, and more than 100 million lowlanders visit mountainous areas above 2500 m annually. The interactions between the low barometric pressure and partial pressure of O2, climate, individual genetic, lifestyle and socio-economic factors, as well as adaptation and acclimatization processes at high elevations are extremely complex. It is challenging to decipher the effects of these myriad factors on the cardiovascular health in high altitude residents, and even more so in those ascending to high altitudes with or without preexisting diseases. This review aims to interpret epidemiological observations in high-altitude populations; present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and more specifically in people with preexisting cardiovascular diseases; the relations between cardiovascular pathologies and neurodegenerative diseases at altitude; the effects of high-altitude exercise; and the putative cardioprotective mechanisms of hypobaric hypoxia.

Store-operated calcium entry: Pivotal roles in renal physiology and pathophysiology.

Research conducted over the last two decades has dramatically advanced the understanding of store-operated calcium channels (SOCC) and their impact on renal function. Kidneys contain many types of cells, including those specialized for glomerular filtration (fenestrated capillary endothelium, podocytes), water and solute transport (tubular epithelium), and regulation of glomerular filtration and renal blood flow (vascular smooth muscle cells, mesangial cells). The highly integrated function of these myriad cells effects renal control of blood pressure, extracellular fluid volume and osmolality, electrolyte balance, and acid-base homeostasis. Many of these cells are regulated by Ca2+ signaling. Recent evidence demonstrates that SOCCs are major Ca2+ entry portals in several renal cell types. SOCC is activated by depletion of Ca2+ stores in the sarco/endoplasmic reticulum, which communicates with plasma membrane SOCC via the Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Orai1 is recognized as the main pore-forming subunit of SOCC in the plasma membrane. Orai proteins alone can form highly Ca2+ selective SOCC channels. Also, members of the Transient Receptor Potential Canonical (TRPC) channel family are proposed to form heteromeric complexes with Orai1 subunits, forming SOCC with low Ca2+ selectivity. Recently, Ca2+ entry through SOCC, known as store-operated Ca2+ entry (SOCE), was identified in glomerular mesangial cells, tubular epithelium, and renovascular smooth muscle cells. The physiological and pathological relevance and the characterization of SOCC complexes in those cells are still unclear. In this review, we summarize the current knowledge of SOCC and their roles in renal glomerular, tubular and vascular cells, including studies from our laboratory, emphasizing SOCE regulation of fibrotic protein deposition. Understanding the diverse roles of SOCE in different renal cell types is essential, as SOCC and its signaling pathways are emerging targets for treatment of SOCE-related diseases.