Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease

Kaplan, Joshua M.; Sharma, Neeraj; Dikdan, Sean

doi:10.3390/ijms19020389

Cited by 76 publications

(40 citation statements)

References 156 publications

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“…It was first discovered by Semenza in 1992 [12]. HIF-1α is a subunit of HIF-1 that accumulates under hypoxic conditions and binds to HIF-1β to form a heterodimer that is transported into the nucleus and binds to hypoxia response elements in the genome, regulating the transcription and expression of a variety of downstream target genes, including the genes related to apoptosis, angiogenesis and tumor metastasis [13, 14]. For example, upregulated HIF-1 expression and altered metabolic pathways are two classical characteristics of cancer.…”

Section: Introductionmentioning

confidence: 99%

Testosterone induces renal tubular epithelial cell death through the HIF-1α/BNIP3 pathway

et al. 2019

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Background The morbidity of nephrolithiasis is 2–3 times higher in males than in females, suggesting that androgen plays a key role in nephrolithiasis. The death of renal tubular epithelial cells (TECs) is an important pathophysiological process contributing to the development of nephrolithiasis. Therefore, the aim of this study is to investigate whether androgen directly induces TECs apoptosis and necrosis and its underlying mechanisms in kidney stone formation. Materials and methods We compared serum testosterone level between male and female healthy volunteers and kidney stone patients. The in vivo nephrolithiasis model was established using glyoxylic acid, and calcium deposits were detected by van Kossa staining. In the in vitro study using mouse TECs (TCMK-1 cells) and human TECs (HK-2 cells), apoptosis, necrosis, and the expression of BH3-only protein Bcl-2-like 19 kDa-interacting protein 3 (BNIP3) were examined incubated with different doses of testosterone using flow cytometry. Levels of apoptosis-related proteins transfected with the BNIP3 siRNA were examined by western blotting. The mitochondrial potential (ΔΨm) was detected by JC-1 staining and flow cytometry. We monitored BNIP3 expression in the testosterone-induced TECs injury model after treatment with hypoxia inducible factor 1α (HIF-1α) and/or hypoxia inducible factor 2α (HIF-2α) inhibitors to determine the upstream protein regulating BNIP3 expression. Additionally, ChIP and luciferase assays were performed to confirm the interaction between HIF-1α and BNIP3. Results Both male and female patients have significantly higher testosterones compared with healthy volunteers. More calcium deposits in the medulla were detected in male mice compared to female and castrated male mice. Testosterone induced TECs apoptosis and necrosis and increased BNIP3 expression in a dose-dependent manner. Testosterone also increased Bax expression, decreased Bcl-2 expression and induced a loss of ΔΨm. This effect was reversed by BNIP3 knockdown. HIF-1α inhibition significantly decreased BNIP3 expression and protected TECs from testosterone-induced apoptosis and necrosis. HIF-2α inhibition, however, did not influence BNIP3 expression or TECs apoptosis or necrosis. Finally, HIF-1α interacted with the BNIP3 promoter region. Conclusion Based on these results, testosterone induced renal TECs death by activating the HIF-1α/BNIP3 pathway. Electronic supplementary material The online version of this article (10.1186/s12967-019-1821-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Testosterone induces renal tubular epithelial cell death through the HIF-1α/BNIP3 pathway

et al. 2019

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“…XDH in the form of most XOR in vivo which generates the reduced form of nicotinamide adenine dinucleotide NAD. Xanthine oxidoreductase could be transformed into xanthine oxidase when it is in a hypoxic environment [26] (Figure 1).…”

Section: A C C E P T E D a R T I C L Ementioning

confidence: 99%

Role of asymptomatic hyperuricemia in the progression of chronic kidney disease and cardiovascular disease

Waheed

Yang

Sun

2021

Korean J Intern Med

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“…Hypoxia-inducible factor (HIF) regulates gene expression in response to hypoxia, including genes involved in erythropoiesis and iron metabolism, promoting iron absorption, iron transport, and heme synthesis (Fig. 1 ) [ 37 ]. Notably, work on the discovery of HIF and its mechanism of action received the 2019 Nobel Prize in Physiology or Medicine.…”

Section: Emerging Alternativesmentioning

confidence: 99%

Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin

2020

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Anemia is a frequent comorbidity of chronic kidney disease (CKD) and is associated with a considerable burden because of decreased patient health-related quality of life and increased healthcare resource utilization. Based on observational data, anemia is associated with an increased risk of CKD progression, cardiovascular events, and all-cause mortality. The current standard of care includes oral or intravenous iron supplementation, erythropoiesis-stimulating agents, and red blood cell transfusion. However, each of these therapies has its own set of population-specific patient concerns, including increased risk of cardiovascular disease, thrombosis, and mortality. Patients receiving dialysis or those who have concurrent diabetes or high blood pressure may be at greater risk of developing these complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Resistance to erythropoiesis-stimulating agents remains a therapeutic challenge in a subset of patients. Hypoxia-inducible factor transcription factors, which regulate several genes involved in erythropoiesis and iron metabolism, can be stabilized by a new class of drugs that act as inhibitors of hypoxia-inducible factor prolyl-hydroxylase enzymes to promote erythropoiesis and elevate hemoglobin levels. Here, we review the burden of anemia of chronic kidney disease, the shortcomings of current standard of care, and the potential practical advantages of hypoxia-inducible factor prolyl-hydroxylase inhibitors in the treatment of patients with anemia of CKD.

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Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease

Cited by 76 publications

References 156 publications

Testosterone induces renal tubular epithelial cell death through the HIF-1α/BNIP3 pathway

Testosterone induces renal tubular epithelial cell death through the HIF-1α/BNIP3 pathway

Role of asymptomatic hyperuricemia in the progression of chronic kidney disease and cardiovascular disease

Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin

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