Editorial: Hypoxia in Kidney Disease

This is the final version. Available on open access from Frontiers Media via the DOI in this record.Introduction Oxygen was first described by Carl Wilhelm Scheele as “Fire air” since it supported combustion. He obtained oxygen by heating mercuric oxide, silver carbonate, and nitrate salts. Scheele communicated his findings to Lavoisier, who realized the significance of this finding. Scheele's discovery of oxygen (ca. 1771) was chronologically earlier than the corresponding work of Priestley and Lavoisier, but he did not publish this discovery until 1777, after both of his rivals had already published their findings (West, 2014). Because others generally are accredited for the discovery of oxygen, and a number of other discoveries, he was nicknamed “hard-luck Scheele.” Oxygen is essential for aerobic metabolism, a fundamental mechanism for energy production. The delivery of optimal levels of oxygen to tissues is tightly regulated as both hypoxia and hyperoxia are detrimental for cellular function. Indeed, tissue hypoxia has been found during pathological conditions such as cancer (Liu et al., 2016), diabetes (Palm et al., 2003), hypertension (Welch et al., 2001), chronic kidney disease (CKD) (Milani et al., 2016), and stroke (Ferdinand and Roffe, 2016). In the 90's Fine et al. proposed kidney hypoxia as a mediator of progressive kidney disease (Fine et al., 1998). Since then, experimental and clinical studies have solidified the view that kidney hypoxia plays a critical role during the genesis and progression of both acute and CKD. This research field is currently at the beginning of integrating pre-clinical with clinical research in which kidney hypoxia related mechanisms are quantified by non-invasive imaging. In combination with the fact that some key questions remain unanswered, this offers exciting new research perspectives that are waiting to be explored. With this Frontiers Research Topic we discuss and identify potential mediators/controllers of hypoxia in kidney disease. If we understand more about the sequence of events leading to kidney hypoxia, its regulation and consequences in renal disease, we might be able to have a major impact in clinical practice. I.e., more accurate and earlier diagnosis, novel treatment targets, and novel therapies.British Heart FoundationEuropean Union, Seventh Framework ProgrammeSwedish Research CouncilSwedish Diabetes Foundatio

Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Hypertension is the largest risk factor for cardiovascular disease, the leading cause of mortality worldwide. As blood pressure regulation is influenced by multiple physiological systems, hypertension cannot be attributed to a single identifiable etiology. Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling, particularly the distal convoluted tubule (DCT)-native, thiazide-sensitive Na–Cl cotransporter (NCC). Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon’s and Gitelman syndromes respectively. Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC. In particular, NCC activity is controlled by phosphorylation/dephosphorylation, and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination. Studies have even found parvalbumin to be an unexpected regulator of the NCC. In recent years, there have been considerable advances in our understanding of NCC control mechanisms, particularly via the pathway containing the with-no-lysine [K] (WNK) and its downstream target kinases, SPS/Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress responsive 1 (OSR1), which has led to the discovery of novel inhibitory molecules. This review summarizes the currently reported regulatory mechanisms of the NCC and discusses their potential as therapeutic targets for treating hypertension.National Institutes of HealthUniversity of Exeter Medical Schoo

The physiology of play: potential relevance for higher education

This is the final version. Available on open access from Taylor & Francis via the DOI in this recordData availability statement: This study did not generate any new data.This paper explores the physiology of a play and its potential for advancing higher education through promoting joy and counteracting performativity, which we argue is a proponent of mental ill-health in the sector. Although a play is increasingly recognised as a fundamental part of the human experience and a successful teaching practice, it is only consistently applied within childhood education. We identify 3 key areas of play physiology relevant for higher education: physical and mental resilience; social intelligence; cognitive flexibility and intellect. We conclude that the incorporation of a play within higher education by developing ‘Playful Universities’ could counteract the fear of failing, avoidance of risk and other negative aspects of performativity and goal-oriented behaviour. Playful learning, therefore, challenges the continued relevance of focusing on a dehumanising and oppressive neoliberal model of performativity-based learning and sheds light on the potential of a joyous, authentic transition to the co-creation of knowledge within higher education.University of Exete

Rhythmic Oxygen Levels Reset Circadian Clocks through HIF1 alpha

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordThe mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in a HIF1α-dependent manner. Furthermore, several clock genes responded to changes in oxygen levels through HIF1α. Finally, we found that a moderate reduction in oxygen levels for a short period accelerates the adaptation of wild-type but not of HIF1α-deficient mice to the new time in a jet lag protocol. We conclude that oxygen, via HIF1α activation, is a resetting cue for circadian clocks and propose oxygen modulation as therapy for jet lag.Israel Science FoundationEuropean Research CouncilFeinberg Graduate School, Weizmann Institute of ScienceBritish Heart FoundationEuropean Union, Seventh Framework Programm

Angiotensin II-induced hypertension in rats is only transiently accompanied by lower renal oxygenation

 This is the final version. Available from Springer Nature via the DOI in this record. Activation of the renin-angiotensin system may initiate chronic kidney disease. We hypothesised that renal hypoxia is a consequence of hemodynamic changes induced by angiotensin II and occurs prior to development of severe renal damage. Male Sprague-Dawley rats were infused continuously with angiotensin II (350 ng/kg/min) for 8 days. Mean arterial pressure (n = 5), cortical (n = 6) and medullary (n = 7) oxygenation (pO2) were continuously recorded by telemetry and renal tissue injury was scored. Angiotensin II increased arterial pressure gradually to 150 ± 18 mmHg. This was associated with transient reduction of oxygen levels in renal cortex (by 18 ± 2%) and medulla (by 17 ± 6%) at 10 ± 2 and 6 ± 1 hours, respectively after starting infusion. Thereafter oxygen levels normalised to pre-infusion levels and were maintained during the remainder of the infusion period. In rats receiving angiotensin II, adding losartan to drinking water (300 mg/L) only induced transient increase in renal oxygenation, despite normalisation of arterial pressure. In rats, renal hypoxia is only a transient phenomenon during initiation of angiotensin II-induced hypertension.British Heart FoundationBritish Heart FoundationDutch Kidney FoundationEuropean Union, Seventh Framework Programm

Perinatal Inhibition of NF-KappaB Has Long-Term Antihypertensive and Renoprotective Effects in Fawn-Hooded Hypertensive Rats

BACKGROUND Inhibition of transcription factor nuclear factor-kappa B (NFκB) is beneficial in various models of hypertension and renal disease. We hypothesized first that NFκB inhibition during renal development ameliorates hereditary hypertensive renal disease and next whether this was mediated via suppression of peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α). METHODS AND RESULTS Prior to the development of renal injury in fawn-hooded hypertensive (FHH) rats, a model of hypertension, glomerular hyperfiltration, and progressive renal injury, NFkB activity, measured by nuclear protein expression of NFkB subunit p65, was enhanced twofold in 2-day-old male and female FHH kidneys as compared to normotensive Wistar-Kyoto (WKY) rats (P <0.05). Treating FHH dams with pyrrolidine di thio carbamate (PDTC), an NFκB inhibitor, from 2 weeks before birth to 4 weeks after birth diminished NFkB activity in 2-day-FHH offspring to 2-day-WKY levels (P <0.01). Perinatal PDTC reduced systolic blood pressure from 20 weeks onwards by on average 25mm Hg (P <0.001) and ameliorated proteinuria (P <0.05) and glomerulosclerosis (P <0.05). In kidneys of 2-day-, 2-week-, and adult offspring of PDTC-treated FHH dams, PGC-1α was induced on average by 67% (quantitative polymerase chain reaction (qPCR)) suggesting that suppression of this factor by NFkB could be involved in renal damage. Follow-up experiments with perinatal pioglitazone (Pio), a PPARγ agonist, failed to confer persistent antihypertensive or renoprotective effects. CONCLUSIONS Perinatal inhibition of enhanced active renal NFκB in 2-day FHH had persistent antihypertensive and renoprotective effects. However, this was not the case for PPARγ stimulation. NFkB stimulation is therefore involved in renal damage in the FHH model of proteinuric renal disease by pathways other than via PPARγ.</p

Hypertension:A problem of organ blood flow supply-demand mismatch

This review introduces a new hypothesis that sympathetically mediated hypertensive diseases are caused, in the most part, by the activation of visceral afferent systems that are connected to neural circuits generating sympathetic activity. We consider how organ hypoperfusion and blood flow supply–demand mismatch might lead to both sensory hyper-reflexia and aberrant afferent tonicity. We discuss how this may drive sympatho-excitatory-positive feedback and extend across multiple organs initiating, or at least amplifying, sympathetic hyperactivity. The latter, in turn, compounds the challenge to sufficient organ blood flow through heightened vasoconstriction that both maintains and exacerbates hypertension

Cooperative Oxygen Sensing by the Kidney and Carotid Body in Blood Pressure Control

This is the author accepted manuscript. The final version is available from Frontiers Media via the DOI in this record.Oxygen sensing mechanisms are vital for homeostasis and survival. When oxygen levels are too low (hypoxia), blood flow has to be increased, metabolism reduced, or a combination of both, to counteract tissue damage. These adjustments are regulated by local, humoral or neural reflex mechanisms. The kidney and the carotid body are both directly sensitive to falls in the partial pressure of oxygen and trigger reflex adjustments and thus act as oxygen sensors. We hypothesize a cooperative oxygen sensing function by both the kidney and carotid body to ensure maintenance of whole body blood flow and tissue oxygen homeostasis. Under pathological conditions of severe or prolonged tissue hypoxia, these sensors may become excessively activated continuously and increase perfusion pressure chronically. Consequently, persistence of their activity could become a driver for the development of hypertension and cardiovascular disease. Hypoxia-mediated renal and carotid body afferent signaling triggers unrestrained activation of the renin angiotensin-aldosterone system (RAAS). Renal and carotid body mediated responses in arterial pressure appear to be synergistic as interruption of either afferent source has a summative effect of reducing blood pressure in renovascular hypertension. We discuss that this cooperative oxygen sensing system can activate/sensitize their own afferent transduction mechanisms via interactions between the RAAS, hypoxia inducible factor and erythropoiesis pathways. This joint mechanism supports our view point that the development of cardiovascular disease involves afferent nerve activation.This work was supported by the British Heart Foundation (FS/14/2/30630, RG/12/6/29670 and PG/15/68/31717) and the European Union, Seventh Framework Programme, Marie Curie Actions (CARPEDIEM - No 612280)

Absence of renal hypoxia in the subacute phase of severe renal ischemia reperfusion injury

 This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this recordTissue hypoxia has been proposed as an important event in renal ischemia reperfusion injury (IRI) particularly during the period of ischemia and in the immediate hours following reperfusion. However, little is known about renal oxygenation during the subacute phase of IRI. We employed four different methods to assess the temporal and spatial changes in tissue oxygenation during the subacute phase (24 h and 5 days after reperfusion) of a severe form of renal IRI in rats. We hypothesized that the kidney is hypoxic 24 h and 5 days after an hour of bilateral renal ischemia, driven by a disturbed balance between renal oxygen delivery (DO2) and oxygen consumption (VO2). Renal DO2 was not significantly reduced in the subacute phase of IRI. In contrast, renal VO2 was 55% less 24 h, and 49% less 5 days after reperfusion than after sham-ischemia. Inner medullary tissue PO2, measured by radiotelemetry was 25 {plus minus} 12% greater 24 h after ischemia than after sham-ischemia. By 5 days after reperfusion, tissue PO2 was similar to that in rats subjected to sham-ischemia. Tissue PO2 measured by Clark electrode was consistently greater 24 h, but not 5 days, after ischemia than after sham-ischemia. Cellular hypoxia, assessed by pimonidazole adduct immunohistochemistry, was largely absent at both time-points and tissue levels of hypoxia inducible factors were downregulated following renal ischemia. Thus, in this model of severe IRI, tissue hypoxia does not appear to be an obligatory event during the subacute phase, likely due to the markedly reduced oxygen consumption.British Heart FoundationBritish Heart FoundationNational Health and Medical Research Council of AustraliaEuropean Union, Seventh Framework Programm