HIF-1α is transcriptionally regulated by NF-κB in acute kidney injury

Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from post-translational hydroxylation, mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia/reperfusion (I/R)-, unilateral ureteral obstruction (UUO)-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, nuclear factor-κB (NF-κB), which plays a central role in inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only in hypoxic condition, but also in normoxic condition. Moreover, the induced HIF-1α by inflammation protected against the tubular injury in AKI. Thus, our findings not only provide novel insight into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.

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Genetic Deletion of Vasohibin-2 Exacerbates Ischemia-Reperfusion-Induced Acute Kidney Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21124545 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4545 ◽

Cited By ~ 1

Author(s):

Hiromasa Miyake ◽

Katsuyuki Tanabe ◽

Satoshi Tanimura ◽

Yuri Nakashima ◽

Tomoyo Morioka ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Diseases ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Neutrophil Infiltration ◽

Endothelial Damage ◽

Tubular Damage ◽

Renal Tubules ◽

Inflammatory Infiltration ◽

Peritubular Capillaries

Acute kidney injury (AKI) has been increasingly recognized as a risk factor for transition to chronic kidney disease. Recent evidence suggests that endothelial damage in peritubular capillaries can accelerate the progression of renal injury. Vasohibin-2 (VASH2) is a novel proangiogenic factor that promotes tumor angiogenesis. However, the pathophysiological roles of VASH2 in kidney diseases remain unknown. In the present study, we examined the effects of VASH2 deficiency on the progression of ischemia–reperfusion (I/R) injury-induced AKI. I/R injury was induced by bilaterally clamping renal pedicles for 25 min in male wild-type (WT) and Vash2 homozygous knockout mice. Twenty-four hours later, I/R injury-induced renal dysfunction and tubular damage were more severe in VASH2-deficient mice than in WT mice, with more prominent neutrophil infiltration and peritubular capillary loss. After induction of I/R injury, VASH2 expression was markedly increased in injured renal tubules. These results suggest that VASH2 expression in renal tubular epithelial cells might be essential for alleviating I/R injury-induced AKI, probably through protecting peritubular capillaries and preventing inflammatory infiltration.

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Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

Frontiers in Immunology ◽

10.3389/fimmu.2020.00734 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 9

Author(s):

Rossana Franzin ◽

Alessandra Stasi ◽

Marco Fiorentino ◽

Giovanni Stallone ◽

Vincenzo Cantaluppi ◽

...

Keyword(s):

Acute Kidney Injury ◽

Complement System ◽

Kidney Diseases ◽

Critical Role ◽

Graft Function ◽

Kidney Injury ◽

Increased Risk ◽

Wide Range ◽

Renal Aging

The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney’s excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16ink4a, Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.

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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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Anaesthesia-Induced Transcriptomic Changes in the Context of Renal Ischemia Uncovered by the Use of a Novel Clamping Device

International Journal of Molecular Sciences ◽

10.3390/ijms22189840 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9840

Author(s):

Charles Verney ◽

David Legouis ◽

Sandrine Placier ◽

Tiffany Migeon ◽

Philippe Bonnin ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion Injury ◽

Kidney Diseases ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Experimental Models ◽

Renal Ischemia ◽

New Device ◽

Rapid Induction ◽

Clamping Device

Ischemia is a common cause of acute kidney injury worldwide, frequently occurring in patients undergoing cardiac surgery or admitted to the intensive care unit (ICU). Thus, ischemia-reperfusion injury (IRI) remains one of the main experimental models for the study of kidney diseases. However, the classical technique, based on non-traumatic surgical clamps, suffers from several limitations. It does not allow the induction of multiple episodes of acute kidney injury (AKI) in the same animal, which would be relevant from a human perspective. It also requires a deep and long sedation, raising the question of potential anaesthesia-related biases. We designed a vascular occluding device that can be activated remotely in conscious mice. We first assessed the intensity and the reproducibility of the acute kidney injury induced by this new device. We finally investigated the role played by the anaesthesia in the IRI models at the histological, functional and transcriptomic levels. We showed that this technique allows the rapid induction of renal ischemia in a repeatable and reproducible manner, breaking several classical limitations. In addition, we used its unique specificities to highlight the renal protective effect conferred by the anaesthesia, related to the mitigation of the IRI transcriptomic program.

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Eriocitrin attenuates ischemia reperfusion-induced oxidative stress and inflammation in rats with acute kidney injury by regulating the dual-specificity phosphatase 14 (DUSP14)-mediated Nrf2 and nuclear factor-κB (NF-κB) pathways

Annals of Translational Medicine ◽

10.21037/atm-21-337 ◽

2021 ◽

Vol 9 (4) ◽

pp. 350-350

Author(s):

Jun Xu ◽

Liang Ma ◽

Ping Fu

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Dual Specificity Phosphatase ◽

Dual Specificity

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RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL-dependent mechanism

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716959115 ◽

2018 ◽

Vol 115 (7) ◽

pp. E1475-E1484 ◽

Cited By ~ 27

Author(s):

Wenjing Liu ◽

Binbin Chen ◽

Yang Wang ◽

Chenling Meng ◽

Huihui Huang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Apical Membrane ◽

Ischemia Reperfusion ◽

Critical Role ◽

Kidney Injury ◽

Tubular Cell ◽

Wild Type ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Proximal Tubular

Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclear whether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK′963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells.

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Gender differences in the susceptibility of hospital-acquired acute kidney injury: more questions than answers

International Urology and Nephrology ◽

10.1007/s11255-020-02526-7 ◽

2020 ◽

Vol 52 (10) ◽

pp. 1911-1914 ◽

Cited By ~ 1

Author(s):

Helmut Schiffl

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Menopausal Status ◽

Kidney Injury ◽

Basic Research ◽

Epidemiological Studies ◽

Experimental Models ◽

Increased Risk ◽

Hospital Acquired

Abstract Hospital-acquired acute kidney injury (HA-AKI) is a heterogeneous renal syndrome which occurs in different clinical settings. It is characterized by multiple aetiologies, various pathogeneses and unpredictable outcomes. HA-AKI, once predominantly viewed as a self-limited and reversible short-term condition, is now recognized as a harbinger for chronic kidney disease and a cause of long-term morbidity with an increased risk of cardiovascular, renal and cancer mortality. Recent clinical studies contradict the generally held belief that female sex is a risk factor for HA-AKI. They show, consistent with basic research performed with experimental models of AKI, that only male sex is associated with HA-AKI. The presence of testosterone, more likely than the absence of estrogen, plays a critical role in sex differences in the susceptibility of ischemia/reperfusion kidney injury. The conflicting data in epidemiological studies related to sex as susceptibility variable for human AKI, underscore the need for more rigorous, well designed observational studies taking into account the menopausal status and hormone therapy.

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