Hypoxia-Inducible Factor and Oxygen Biology in the Kidney

Kidney tissue hypoxia is detected in various kidney diseases and is considered to play an important role in the pathophysiology of both AKI and CKD. Because of the characteristic vascular architecture and high energy demand to drive tubular solute transport, the renal medulla is especially prone to hypoxia. Injured kidneys often present capillary rarefaction, inflammation, and fibrosis, which contribute to sustained kidney hypoxia, forming a vicious cycle promoting progressive CKD. Hypoxia-inducible factor (HIF), a transcription factor responsible for cellular adaptation to hypoxia, is generally considered to protect against AKI. On the contrary, consequences of sustained HIF activation in CKD may be either protective, neutral, or detrimental. The kidney outcomes seem to be affected by various factors, such as cell types in which HIF is activated/inhibited, disease models, balance between two HIF isoforms, and time and methods of intervention. This suggests multifaceted functions of HIF and highlights the importance of understanding its role within each specific context. Prolyl-hydroxylase domain (PHD) inhibitors, which act as HIF stabilizers, have been developed to treat anemia of CKD. Although many preclinical studies demonstrated renoprotective effects of PHD inhibitors in CKD models, there may be some situations in which they lead to deleterious effects. Further studies are needed to identify patients who would gain additional benefits from PHD inhibitors and those who may need to avoid them.

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Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

International Journal of Molecular Sciences ◽

10.3390/ijms22115703 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5703

Author(s):

Vittoria Infantino ◽

Anna Santarsiero ◽

Paolo Convertini ◽

Simona Todisco ◽

Vito Iacobazzi

Keyword(s):

Cancer Cells ◽

Energy Demand ◽

Molecular Mechanisms ◽

Cell Metabolism ◽

Hypoxia Inducible Factor ◽

Cancer Therapeutics ◽

High Energy ◽

Metabolic Reprogramming ◽

Low Oxygen ◽

Functional Changes

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

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Competitive HIF Prolyl Hydroxylase Inhibitors Show Protection against Oxidative Stress by a Mechanism Partially Dependent on Glycolysis

ISRN Neuroscience ◽

10.1155/2013/598587 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Ann-Louise Bergström ◽

Karina Fog ◽

Thomas Nikolaj Sager ◽

Anne Techau Bruun ◽

Kenneth Thirstrup

Keyword(s):

Oxidative Stress ◽

Hypoxia Inducible Factor ◽

Large Degree ◽

Cell Types ◽

Prolyl Hydroxylase ◽

Adaptation To Hypoxia ◽

Cellular Effects ◽

Competitive Inhibitors ◽

Inhibitor Compounds ◽

Hif Prolyl Hydroxylase

The hypoxia inducible factor 1 (HIF-1) is a central transcription factor involved in the cellular and molecular adaptation to hypoxia and low glucose supply. The level of HIF-1 is to a large degree regulated by the HIF prolyl hydroxylase enzymes (HPHs) belonging to the Fe(II) and 2-oxoglutarate-dependent dioxygenase superfamily. In the present study, we compared competitive and noncompetitive HPH-inhibitor compounds in two different cell types (SH-SY5Y and PC12). Although the competitive HPH-inhibitor compounds were found to be pharmacologically more potent than the non-competitive compounds at inhibiting HPH2 and HPH1, this was not translated into the cellular effects of the compounds, where the non-competitive inhibitors were actually more potent than the competitive in stabilizing and translocatingHIF1αto the nucleus (quantified with Cellomics ArrayScan technology). This could be explained by the high cellular concentrations of the cofactor 2-oxoglutarate (2-OG) as the competitive inhibitors act by binding to the 2-OG site of the HPH enzymes. Both competitive and non-competitive HPH inhibitors protected the cells against 6-OHDA induced oxidative stress. In addition, the protective effect of a specific HPH inhibitor was partially preserved when the cells were serum starved and exposed to 2-deoxyglucose, an inhibitor of glycolysis, indicating that other processes than restoring energy supply could be important for the HIF-mediated cytoprotection.

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Role of Endothelial Prolyl-4-Hydroxylase Domain Protein/Hypoxia-Inducible Factor Axis in Acute Kidney Injury

Nephron ◽

10.1159/000518632 ◽

2021 ◽

pp. 1-6

Author(s):

Ratnakar Tiwari ◽

Pinelopi P. Kapitsinou

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hypoxia Inducible Factor ◽

Kidney Injury ◽

Cell Types ◽

Endothelial Damage ◽

Adaptation To Hypoxia ◽

Low Oxygen

Ischemia reperfusion injury (IRI) results from a cessation or restriction of blood supply to an organ followed by reestablishment of perfusion and reoxygenation. In the kidney, IRI due to transplantation, cardiac surgery with cardiopulmonary bypass, and other major vascular surgeries contributes to acute kidney injury (AKI), a clinical condition associated with significant morbidity and mortality in hospitalized patients. In the postischemic kidney, endothelial damage promotes inflammatory responses and leads to persistent hypoxia of the renal tubular epithelium. Like other cell types, endothelial cells respond to low oxygen tension by multiple hypoxic signaling mechanisms. Key mediators of adaptation to hypoxia are hypoxia-inducible factors (HIF)-1 and -2, transcription factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). The PHD/HIF axis controls several processes determining injury outcome, including ATP generation, cell survival, proliferation, and angiogenesis. Here, we discuss recent advances in our understanding of the endothelial-derived PHD/HIF signaling and its effects on postischemic AKI.

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Targeting Microglial KATPChannels to Treat Neurodegenerative Diseases: A Mitochondrial Issue

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/194546 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 19

Author(s):

Manuel J. Rodríguez ◽

Margot Martínez-Moreno ◽

Francisco J. Ortega ◽

Nicole Mahy

Keyword(s):

Energy Demand ◽

Dynamic Equilibrium ◽

Cell Types ◽

High Energy ◽

Mitochondrial Activity ◽

Matrix Remodeling ◽

Cellular Processes ◽

Neurodegenerative Process ◽

Response Capacity ◽

Unique Cell

Neurodegeneration is a complex process involving different cell types and neurotransmitters. A common characteristic of neurodegenerative disorders is the occurrence of a neuroinflammatory reaction in which cellular processes involving glial cells, mainly microglia and astrocytes, are activated in response to neuronal death. Microglia do not constitute a unique cell population but rather present a range of phenotypes closely related to the evolution of neurodegeneration. In a dynamic equilibrium with the lesion microenvironment, microglia phenotypes cover from a proinflammatory activation state to a neurotrophic one directly involved in cell repair and extracellular matrix remodeling. At each moment, the microglial phenotype is likely to depend on the diversity of signals from the environment and of its response capacity. As a consequence, microglia present a high energy demand, for which the mitochondria activity determines the microglia participation in the neurodegenerative process. As such, modulation of microglia activity by controlling microglia mitochondrial activity constitutes an innovative approach to interfere in the neurodegenerative process. In this review, we discuss the mitochondrial KATPchannel as a new target to control microglia activity, avoid its toxic phenotype, and facilitate a positive disease outcome.

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Changes in lipid peroxidation during pregnancy and after delivery in rats: effect of pinealectomy

Reproduction ◽

10.1530/reprod/119.1.143 ◽

2000 ◽

pp. 143-149 ◽

Cited By ~ 9

Author(s):

RM Sainz ◽

RJ Reiter ◽

JC Mayo ◽

J Cabrera ◽

DX Tan ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Oxidative Damage ◽

Energy Demand ◽

Physiological State ◽

High Energy ◽

Free Radical Scavengers ◽

Radical Scavengers ◽

Oxygen Requirement ◽

Pregnant Rats

Pregnancy is a physiological state accompanied by a high energy demand of many bodily functions and an increased oxygen requirement. Because of the increased intake and utilization of oxygen, increased levels of oxidative stress would be expected. In the present study, the degree of lipid peroxidation was examined in different tissues from non-pregnant and pregnant rats after the delivery of their young. Melatonin and other indole metabolites are known to be direct free radical scavengers and indirect antioxidants. Thus the effect of pinealectomy at 1 month before pregnancy on the accumulation of lipid damage was investigated in non-pregnant and pregnant rats after the delivery of their young. Malonaldehyde and 4-hydroxyalkenal concentrations were measured in the lung, uterus, liver, brain, kidney, thymus and spleen from intact and pinealectomized pregnant rats soon after birth of their young and at 14 and 21 days after delivery. The same parameters were also evaluated in intact and pinealectomized non-pregnant rats. Shortly after delivery, lipid oxidative damage was increased in lung, uterus, brain, kidney and thymus of the mothers. No differences were detected in liver and spleen. Pinealectomy enhanced this effect in the uterus and lung. It is concluded that during pregnancy high levels of oxidative stress induce an increase in oxidative damage to lipids, which in some cases is inhibited by the antioxidative actions of pineal indoles.

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The Quorum Sensing Auto-Inducer 2 (AI-2) Stimulates Nitrogen Fixation and Favors Ethanol Production over Biomass Accumulation in Zymomonas mobilis

International Journal of Molecular Sciences ◽

10.3390/ijms22115628 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5628

Author(s):

Valquíria Campos Alencar ◽

Juliana de Fátima dos Santos Silva ◽

Renata Ozelami Vilas Boas ◽

Vinícius Manganaro Farnézio ◽

Yara N. L. F. de Maria ◽

...

Keyword(s):

Nitrogen Fixation ◽

Quorum Sensing ◽

Ethanol Production ◽

N2 Fixation ◽

Energy Demand ◽

Zymomonas Mobilis ◽

Biomass Accumulation ◽

High Energy ◽

Gram Negative ◽

Expression Of Genes

Autoinducer 2 (or AI-2) is one of the molecules used by bacteria to trigger the Quorum Sensing (QS) response, which activates expression of genes involved in a series of alternative mechanisms, when cells reach high population densities (including bioluminescence, motility, biofilm formation, stress resistance, and production of public goods, or pathogenicity factors, among others). Contrary to most autoinducers, AI-2 can induce QS responses in both Gram-negative and Gram-positive bacteria, and has been suggested to constitute a trans-specific system of bacterial communication, capable of affecting even bacteria that cannot produce this autoinducer. In this work, we demonstrate that the ethanologenic Gram-negative bacterium Zymomonas mobilis (a non-AI-2 producer) responds to exogenous AI-2 by modulating expression of genes involved in mechanisms typically associated with QS in other bacteria, such as motility, DNA repair, and nitrogen fixation. Interestingly, the metabolism of AI-2-induced Z. mobilis cells seems to favor ethanol production over biomass accumulation, probably as an adaptation to the high-energy demand of N2 fixation. This opens the possibility of employing AI-2 during the industrial production of second-generation ethanol, as a way to boost N2 fixation by these bacteria, which could reduce costs associated with the use of nitrogen-based fertilizers, without compromising ethanol production in industrial plants.

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IoT Platform for Energy Sustainability in University Campuses

Sensors ◽

10.3390/s21020357 ◽

2021 ◽

Vol 21 (2) ◽

pp. 357

Author(s):

Pedro Moura ◽

José Ignacio Moreno ◽

Gregorio López López ◽

Manuel Alvarez-Campana

Keyword(s):

Energy Demand ◽

New Technologies ◽

Low Cost ◽

Sustainable Use ◽

High Energy ◽

Appropriate Technology ◽

Monitoring And Control ◽

Energy Sustainability ◽

University Campuses ◽

Iot Platform

University campuses are normally constituted of large buildings responsible for high energy demand, and are also important as demonstration sites for new technologies and systems. This paper presents the results of achieving energy sustainability in a testbed composed of a set of four buildings that constitute the Telecommunications Engineering School of the Universidad Politécnica de Madrid. In the paper, after characterizing the consumption of university buildings for a complete year, different options to achieve more sustainable use of energy are presented, considering the integration of renewable generation sources, namely photovoltaic generation, and monitoring and controlling electricity demand. To ensure the implementation of the desired monitoring and control, an internet of things (IoT) platform based on wireless sensor network (WSN) infrastructure was designed and installed. Such a platform supports a smart system to control the heating, ventilation, and air conditioning (HVAC) and lighting systems in buildings. Furthermore, the paper presents the developed IoT-based platform, as well as the implemented services. As a result, the paper illustrates how providing old existing buildings with the appropriate technology can contribute to the objective of transforming such buildings into nearly zero-energy buildings (nZEB) at a low cost.

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High-throughput screening of circRNAs reveals novel mechanisms of tuberous sclerosis complex-related renal angiomyolipoma

Human Genomics ◽

10.1186/s40246-021-00344-1 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Yang Zhao ◽

Hao Guo ◽

Wenda Wang ◽

Guoyang Zheng ◽

Zhan Wang ◽

...

Keyword(s):

Lipid Metabolism ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Regulatory Network ◽

High Throughput Screening ◽

Kidney Tissue ◽

Cell Types ◽

The Body ◽

Differentially Expressed ◽

Renal Angiomyolipoma

Abstract Objective Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by lesions throughout the body. Our previous study showed the abnormal up-regulation of miRNAs plays an important part in the pathogenesis of TSC-related renal angiomyolipoma (TSC-RAML). circRNAs were known as important regulators of miRNA, but little is known about the circRNAs in TSC-RAMLs. Methods Microarray chips and RNA sequencing were used to identify the circRNAs and mRNAs that were differently expressed between the TSC-RAML and normal kidney tissue. A competitive endogenous RNA (ceRNA) regulatory network was constructed to reveal the regulation of miRNAs and mRNAs by the circRNAs. The biological functions of circRNA and mRNA were analyzed by pathway analysis. Microenvironmental cell types were estimated with the MCP-counter package. Results We identified 491 differentially expressed circRNAs (DECs) and 212 differentially expressed genes (DEGs), and 6 DECs were further confirmed by q-PCR. A ceRNA regulatory network which included 6 DECs, 5 miRNAs, and 63 mRNAs was established. Lipid biosynthetic process was significantly up-regulated in TSC-RAML, and the humoral immune response and the leukocyte chemotaxis pathway were found to be down-regulated. Fibroblasts are enriched in TSC-RAML, and the up-regulation of circRNA_000799 and circRNA_025332 may be significantly correlated to the infiltration of the fibroblasts. Conclusion circRNAs may regulate the lipid metabolism of TSC-RAML by regulation of the miRNAs. Fibroblasts are enriched in TSC-RAMLs, and the population of fibroblast may be related to the alteration of circRNAs of TSC-RAML. Lipid metabolism in fibroblasts is a potential treatment target for TSC-RAML.

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Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases

Cells ◽

10.3390/cells10061413 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1413

Author(s):

Tjessa Bondue ◽

Fanny O. Arcolino ◽

Koenraad R. P. Veys ◽

Oyindamola C. Adebayo ◽

Elena Levtchenko ◽

...

Keyword(s):

Epithelial Cells ◽

Kidney Diseases ◽

Cell Types ◽

Cell Models ◽

Tubular Epithelial Cells ◽

Disease Mechanisms ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Disease Cell

Epithelial cells exfoliated in human urine can include cells anywhere from the urinary tract and kidneys; however, podocytes and proximal tubular epithelial cells (PTECs) are by far the most relevant cell types for the study of genetic kidney diseases. When maintained in vitro, they have been proven extremely valuable for discovering disease mechanisms and for the development of new therapies. Furthermore, cultured patient cells can individually represent their human sources and their specific variants for personalized medicine studies, which are recently gaining much interest. In this review, we summarize the methodology for establishing human podocyte and PTEC cell lines from urine and highlight their importance as kidney disease cell models. We explore the well-established and recent techniques of cell isolation, quantification, immortalization and characterization, and we describe their current and future applications.

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Sigma-1 Receptor Promotes Mitochondrial Bioenergetics by Orchestrating ER Ca2+ Leak during Early ER Stress

Metabolites ◽

10.3390/metabo11070422 ◽

2021 ◽

Vol 11 (7) ◽

pp. 422

Author(s):

Zhanat Koshenov ◽

Furkan E. Oflaz ◽

Martin Hirtl ◽

Johannes Pilic ◽

Olaf A. Bachkoenig ◽

...

Keyword(s):

Er Stress ◽

Energy Demand ◽

Molecular Mechanisms ◽

High Energy ◽

Human Neuroblastoma Cell ◽

Mitochondrial Bioenergetics ◽

Dependent Manner ◽

Human Neuroblastoma ◽

Sigma 1 Receptor ◽

Sigma 1

The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.

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