Hypoxia-Driven Responses in Chronic Kidney Disease

Miguel, Verónica; Rojo, Ana I.

doi:10.3390/oxygen3030020

Cited by 4 publications

(3 citation statements)

References 211 publications

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“…A recent study has demonstrated that hypoxia, characterized by low cellular oxygen concentrations, activates APOL1 transcription in kidney podocytes and tubular cells [ 38 ]. This finding aligns with the known role of renal hypoxia in kidney injury and repair and the pathogenesis of CKD and ESRD [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. The innate vulnerability of kidneys to hypoxia is attributed to their vascular structure and high-energy-demanding functions [ 47 ].…”

Section: Introductionsupporting

confidence: 87%

IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions

Randle,

Amara,

Popik

2024

IJMS

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Genetic variants in the protein-coding regions of APOL1 are associated with an increased risk and progression of chronic kidney disease (CKD) in African Americans. Hypoxia exacerbates CKD progression by stabilizing HIF-1α, which induces APOL1 transcription in kidney podocytes. However, the contribution of additional mediators to regulating APOL1 expression under hypoxia in podocytes is unknown. Here, we report that a transient accumulation of HIF-1α in hypoxia is sufficient to upregulate APOL1 expression in podocytes through a cGAS/STING/IRF3-independent pathway. Notably, IFI16 ablation impedes hypoxia-driven APOL1 expression despite the nuclear accumulation of HIF-1α. Co-immunoprecipitation assays indicate no direct interaction between IFI16 and HIF-1α. Our studies identify hypoxia response elements (HREs) in the APOL1 gene enhancer/promoter region, showing increased HIF-1α binding to HREs located in the APOL1 gene enhancer. Luciferase reporter assays confirm the role of these HREs in transcriptional activation. Chromatin immunoprecipitation (ChIP)–qPCR assays demonstrate that IFI16 is not recruited to HREs, and IFI16 deletion reduces HIF-1α binding to APOL1 HREs. RT-qPCR analysis indicates that IFI16 selectively affects APOL1 expression, with a negligible impact on other hypoxia-responsive genes in podocytes. These findings highlight the unique contribution of IFI16 to hypoxia-driven APOL1 gene expression and suggest alternative IFI16-dependent mechanisms regulating APOL1 gene expression under hypoxic conditions.

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Section: Introductionsupporting

confidence: 87%

IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions

Randle,

Amara,

Popik

2024

IJMS

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“…A lack of oxygen usually induces anaerobic metabolism in the cells; however, in some parts of the kidney, such as proximal tubules, this metabolic pathway is unable to meet the high energy demands of the kidneys. Moreover, a lack of ATP interrupts normal Na + , Ca 2+ , and K + transport through the cellular membrane, which leads to calcium overload, the generation of reactive oxygen species, and the opening of mitochondrial permeability transition pores after reoxygenation or reperfusion, all of which leads to the loss of tubular epithelial cells [ 4 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Hypoxia/Reoxygenation Induces Mitochondrial Cardiolipin Remodeling in Human Kidney Cells

Strazdauskas,

Trumbeckaite,

Jakstas

et al. 2024

IJMS

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Renal ischemia/reperfusion is a serious condition that not only causes acute kidney injury, a severe clinical syndrome with high mortality, but is also an inevitable part of kidney transplantation or other kidney surgeries. Alterations of oxygen levels during ischemia/reperfusion, namely hypoxia/reoxygenation, disrupt mitochondrial metabolism and induce structural changes that lead to cell death. A signature mitochondrial phospholipid, cardiolipin, with many vital roles in mitochondrial homeostasis, is one of the key players in hypoxia/reoxygenation-induced mitochondrial damage. In this study, we analyze the effect of hypoxia/reoxygenation on human renal proximal tubule epithelial cell (RPTEC) cardiolipins, as well as their metabolism and mitochondrial functions. RPTEC cells were placed in a hypoxic chamber with a 2% oxygen atmosphere for 24 h to induce hypoxia; then, they were replaced back into regular growth conditions for 24 h of reoxygenation. Surprisingly, after 24 h, hypoxia cardiolipin levels substantially increased and remained higher than control levels after 24 h of reoxygenation. This was explained by significantly elevated levels of cardiolipin synthase and lysocardiolipin acyltransferase 1 (LCLAT1) gene expression and protein levels. Meanwhile, hypoxia/reoxygenation decreased ADP-dependent mitochondrial respiration rates and oxidative phosphorylation capacity and increased reactive oxygen species generation. Our findings suggest that hypoxia/reoxygenation induces cardiolipin remodeling in response to reduced mitochondrial oxidative phosphorylation in a way that protects mitochondrial function.

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“…Patients with CKD develop hypoxia due to increased incidence of cardiovascular diseases, reducing the supply of oxygen to the tissues. Additional factors of tissue hypoxia include anemia, hyperglycemia, hypertension, smoking, hypercholesterolemia, and atherosclerosis [ 13 ]. Under hypoxic conditions, the elements contribute to the initiation of the apoptosis pathway, fibroblast and leukocyte activation, and subsequent extracellular matrix deposition (ECM).…”

Section: Introductionmentioning

confidence: 99%

Changes of Dissociative Properties of Hemoglobin in Patients with Chronic Kidney Disease

Korus,

Wydro,

Gołębiowski

et al. 2024

Diagnostics

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Background: The ability of hemoglobin to bind and dissociate oxygen is crucial in delivering oxygen to tissues and is influenced by a range of physiological states, compensatory mechanisms, and pathological conditions. This may be illustrated by the oxyhemoglobin dissociation curve (ODC). The key parameter for evaluating the oxygen affinity to hemoglobin is p50. The aim of this study was to evaluate the impact of hemodialysis on p50 in a group of patients with chronic kidney disease (CKD). An additional goal was to assess the correlation between p50 and the parameters of erythropoiesis, point-of-care testing (POCT), and other laboratory parameters. Methods: One hundred and eighty patients (106 male, 74 female), mean age 62.5 ± 17 years, with CKD stage G4 and G5 were enrolled in this cross-sectional study. Patients were divided into two groups, including 65 hemodialysis (HD) patients and 115 patients not receiving dialysis (non-HD). During the standard procedure of arteriovenous fistula creation, blood samples from the artery (A) and the vein (V) were taken for POCT. The causes of CKD, as well as demographic and comorbidity data, were obtained from medical records and direct interviews. Results: The weekly dose of erythropoietin was higher in HD patients than in non-HD patients (4914 ± 2253 UI vs. 403 ± 798 UI, p < 0.01), but hemoglobin levels did not differ between these groups. In the group of non-HD patients, more advanced metabolic acidosis (MA) was found, compared to the group with HD. In arterial and venosus blood samples, the non-HD group had significantly lower pH, pCO2 and HCO3−. This group had a higher proportion of individuals with MA with HCO3− < 22 mmol/L (42% vs. 24%, p < 0.01). The absolute difference of p50 in arterial and venous blood was determined using the formula Δp50 = (p50-A) − (p50-V). Δp50 was significantly higher in the HD group in comparison to non-HD (0.08 ± 2.05 mmHg vs. −0.66 ± 1.93 mmHg, p = 0,02). There was a negative correlation between pH and the p50 value in arterial (pH-A vs. p50-A, r = −0.56, p < 0.01) and venous blood (pH-V vs. p50-V, r = −0.45, p < 0.01). In non-HD patients, hemoglobin levels correlated negatively with p50 (r = −0.29, p < 0.01), whereas no significant relation was found in HD patients. Conclusions: The ODC in pre-dialysis CKD (non-HD) patients is shifted to the right due to MA, and this is an additional factor influencing erythropoiesis. Hemodialysis restores the natural differences in hemoglobin’s dissociation characteristics in the arterial and venous circulation.

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Hypoxia-Driven Responses in Chronic Kidney Disease

Cited by 4 publications

References 211 publications

IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions

IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions

In Vitro Hypoxia/Reoxygenation Induces Mitochondrial Cardiolipin Remodeling in Human Kidney Cells

Changes of Dissociative Properties of Hemoglobin in Patients with Chronic Kidney Disease

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