Hypoxia-Inducible Factors in Acute Kidney Injury: From Pathophysiology to a Novel Approach of Organ Protection

Abstract Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague–Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.

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Ceria-Zirconia Antioxidant Nanoparticles Attenuate Hypoxia-Induced Acute Kidney Injury by Restoring Autophagy Flux and Alleviating Mitochondrial Damage

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2020.2948 ◽

2020 ◽

Vol 16 (7) ◽

pp. 1144-1159

Author(s):

Sang-Eun Hong ◽

Jong Hun An ◽

Seong-Lan Yu ◽

Jaeku Kang ◽

Chang Gyo Park ◽

...

Keyword(s):

Acute Kidney Injury ◽

Free Radical ◽

Antioxidant Activities ◽

Kidney Injury ◽

Mitochondrial Damage ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Autophagy Flux ◽

Novel Approach

Oxidative stress is one of the principal causes of hypoxia-induced kidney injury. The ceria nanoparticle (CNP) is known to exhibit free radical scavenger and catalytic activities. When zirconia is attached to CNPs (CZNPs), the ceria atom tends to remain in a Ce3+ form and its efficacy as a free radical scavenger thus increases. We determined the effectiveness of CNP and CZNP antioxidant activities against hypoxia-induced acute kidney injury (AKI) and observed that these nanoparticles suppress the apoptosis of hypoxic HK-2 cells by restoring autophagy flux and alleviating mitochondrial damage. In vivo experiments revealed that CZNPs effectively attenuate hypoxia-induced AKI by preserving renal structures and glomerulus function. These nanoparticles can successfully diffuse into HK-2 cells and effectively counteract reactive oxygen species (ROS) to block hypoxia-induced AKI. This suggests that these particles represent a novel approach to controlling this condition.

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New Biomarkers in Acute Tubulointerstitial Nephritis: A Novel Approach to a Classic Condition

International Journal of Molecular Sciences ◽

10.3390/ijms21134690 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4690 ◽

Cited By ~ 1

Author(s):

Laura Martinez Valenzuela ◽

Juliana Draibe ◽

Xavier Fulladosa ◽

Juan Torras

Keyword(s):

Acute Kidney Injury ◽

Tubulointerstitial Nephritis ◽

Kidney Injury ◽

Special Focus ◽

Nucleotide Polymorphisms ◽

Acute Tubulointerstitial Nephritis ◽

Non Invasive ◽

Cytokines And Chemokines ◽

Novel Approach ◽

New Biomarkers

Acute tubulointerstitial nephritis (ATIN) is an immunomediated cause of acute kidney injury. The prevalence of ATIN among the causes of acute kidney injury (AKI) is not negligible, especially those cases related to certain drugs. To date, there is a lack of reliable non-invasive diagnostic and follow-up markers. The gold standard for diagnosis is kidney biopsy, which shows a pattern of tubulointerstitial leukocyte infiltrate. The urinalysis findings can aid in the diagnosis but are no longer considered sensitive or specific. Atthe present time, there is a rising attentiveness tofinding trustworthy biomarkers of the disease, with special focus in urinary cytokines and chemokines that may reflect kidney local inflammation. Cell-based tests are of notable interest to identify the exact drug involved in hypersensitivity reactions to drugs, manifesting as ATIN. Certain single-nucleotide polymorphisms in HLA or cytokine genes may confer susceptibility to the disease according to pathophysiological basis. In this review, we aim to critically examine and summarize the available evidence on this topic.

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Role of Hypoxia-Inducible Factors in Acute Kidney Injury

Nephron Clinical Practice ◽

10.1159/000363669 ◽

2014 ◽

Vol 127 (1-4) ◽

pp. 70-74 ◽

Cited By ~ 10

Author(s):

Kelly K. Andringa ◽

Anupam Agarwal

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Hypoxia Inducible Factors

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Hypoxia-inducible factor and renal disorders

10.1093/med/9780199592548.003.0331 ◽

2015 ◽

Author(s):

Thomas Connor ◽

Patrick H. Maxwell

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Transcription Factors ◽

Cellular Response ◽

Hypoxia Inducible Factor ◽

Kidney Injury ◽

The Body ◽

Hypoxia Inducible Factors ◽

Low Levels ◽

Homeostatic Response

Hypoxia-inducible factors (HIFs) are transcription factors that control the cellular response to changes in oxygen levels. This response is common to all cells in the body and is highly conserved in evolution. The kidney exhibits steep gradients in oxygenation which are important in the homeostatic response to anaemia. The cellular response to low levels of oxygen (hypoxia) also plays a role in such diverse processes as acute kidney injury, the progression of chronic kidney disease, and kidney cancer. There is now considerable interest in using drugs to manipulate the HIF response to treat these varied conditions.

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Role of Damage-Associated Molecular Patterns in Septic Acute Kidney Injury, From Injury to Recovery

Frontiers in Immunology ◽

10.3389/fimmu.2021.606622 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pierre-Olivier Ludes ◽

Charles de Roquetaillade ◽

Benjamin Glenn Chousterman ◽

Julien Pottecher ◽

Alexandre Mebazaa

Keyword(s):

Acute Kidney Injury ◽

Tissue Injury ◽

High Mobility ◽

Kidney Injury ◽

Blood Perfusion ◽

Tubular Damage ◽

Organ Protection ◽

Tubular Necrosis ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus [histones, high-mobility group box 1 protein (HMGB1)] and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.

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