Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signalling on its function remains scarcely understood. Here, we reveal that deficiency of HIF (Hypoxia Inducible Factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Concomitant loss of PHD2 in renal erythropoietin (EPO) producing cells stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis) and systemic hypoglycaemia. Using mouse lines displaying only EPO-induced erythrocytosis or anaemia, we show that hypo- or hyperglycaemia is necessary and sufficient to respectively enhance or reduce exocytosis of epinephrine from the adrenal gland. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla and beyond regulates both synthesis and release of catecholamines, especially epinephrine. Our findings are also of great significance in view of the small molecule PHD inhibitors being tested in phase III global clinical development trials for use in renal anaemia patients.

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Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland

Watts¹,

Bechmann

Meneses

et al. 2020

Preprint

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Murine trypanosomiasis recapitulates transcriptomic features of acute kidney injury

Ogunsola,

Cooper,

Quintana

et al. 2024

Preprint

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The African trypanosome, Trypanosoma brucei, disseminates systemically in tissues of the infected host resulting in complex immunopathology. The kidneys which are important in the response to the anaemia characteristic of African trypanosomiasis, are prone to acute kidney injury (AKI) from multiple noxious stimuli. Little is known about the transcriptional responses of the kidney to trypanosome infection. To assess the tissue-specific response to infection with Trypanosoma brucei, we profiled the clinicopathologic and transcriptional responses of the kidney in BALB/C (susceptible) and C57BL/6 (tolerant) murine models, at early (7 dpi) and late (21 dpi) time points of infection. Trypanosomes in the renal interstitium, tubular necrosis and inflammation characterised early infection in both mouse strains. By late infection, we observed extensive tubular necrosis in the susceptible BALB/C but reparative tubular regeneration in the tolerant C57BL/6 mice. T.b. brucei infection resulted in significant increases in serum creatinine in both strains. Consistent with the clinicopathologic findings, RNA-seq detected both mouse strain- and time-dependent transcriptional responses in the kidney. These included perturbations in genes associated with solute/ion transport, upregulation of markers of tubular injury, hypoxia, glycolysis, and a profound inflammatory and immune response, mirroring the responses observed in other models of AKI. Differential tissue pathology at late time point is preceded by expansion of CD8+ T cells, profound expression of transcription factors and upregulation of anti-inflammatory pathways in C57BL/6 mice. Our findings demonstrate that experimental T. brucei infection-induced kidney injury (TIKI) is a model of AKI and may have clinical implications for Human African Trypanosomiasis cases, who currently are not routinely screened for markers of kidney function.

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The Overlap Syndrome of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease: A Systematic Review

et al. 2022

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Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are common diseases that strongly impact the quality and length of life. Their coexistence is determined by overlap syndrome (OS). This systematic review aims to define the significance of these comorbidities according to the current state of knowledge. For this systematic review, we searched PubMed, Scopus, and Cochrane for studies published between 2018 and 26 October 2022, to find original, observational, human studies published in English, where the diagnosis of COPD was according to the Global Initiative for Obstructive Lung Disease guidelines and the diagnosis of OSA was based on polysomnography. The quality of studies was assessed using the Newcastle–Ottawa quality assessment tool for cohort and case–control studies, as well as its modification for cross-sectional studies. Of the 1548 records identified, 38 were eligible and included in this systematic review. The included studies covered a total population of 27,064 participants. This paper summarizes the most important, up-to-date information regarding OS, including the prevalence, meaning of age/gender/body mass index, polysomnography findings, pulmonary function, comorbidities, predicting OSA among COPD patients, and treatment of this syndrome.

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Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

Cited by 6 publications

References 159 publications

Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland

Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland

Murine trypanosomiasis recapitulates transcriptomic features of acute kidney injury

The Overlap Syndrome of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease: A Systematic Review

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