Indoxyl glucuronide, a protein-bound uremic toxin, inhibits hypoxia-inducible factor‒dependent erythropoietin expression through activation of aryl hydrocarbon receptor

Asai, Hirobumi; Hirata, Junya; Watanabe-Akanuma, Mie

doi:10.1016/j.bbrc.2018.09.018

Cited by 25 publications

(12 citation statements)

References 29 publications

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“…Many tryptophan-derived uremic toxins, including IAA, IS, kynurenine, and indoxyl glucuronide, activate the aryl hydrocarbon receptor (AhR), which is a ligand-activated transcription factor that mediates toxic and inflammatory responses [ 56 , 57 , 58 ]. Activated AhR increases the expression of proinflammatory and oxidative stress cell markers such as vascular cell-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) [ 59 ].…”

Section: Pbut Derivation and Pathological Mechanismsmentioning

confidence: 99%

Gut-Derived Protein-Bound Uremic Toxins

Graboski

Redinbo

2020

Toxins

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Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

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Section: Pbut Derivation and Pathological Mechanismsmentioning

confidence: 99%

Gut-Derived Protein-Bound Uremic Toxins

Graboski

Redinbo

2020

Toxins

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“…Kynurenine activates ARNT and competes with HIF-2α to prevent its binding to HIF-β, thereby decreasing EPO production. Similarly, in CKD, a uremic toxin, indoxyl-sulfate, apart from simulating hepcidin expression [78], may also activate ARNT to suppress EPO production [79]. Consequently, an elevated hepcidin level is caused by a medley of interacting factors, such as inflammation, excess iron, decreased EPO/erythropoiesis or metabolites or products of certain processes or pathways of systemic metabolism (Figure 1).…”

Section: Anemia Of Chronic Kidney Diseasementioning

confidence: 99%

Anemia of Inflammation with An Emphasis on Chronic Kidney Disease

Begum

Latunde-Dada

2019

Nutrients

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Iron is vital for a vast variety of cellular processes and its homeostasis is strictly controlled and regulated. Nevertheless, disorders of iron metabolism are diverse and can be caused by insufficiency, overload or iron mal-distribution in tissues. Iron deficiency (ID) progresses to iron-deficiency anemia (IDA) after iron stores are depleted. Inflammation is of diverse etiology in anemia of chronic disease (ACD). It results in serum hypoferremia and tissue hyperferritinemia, which are caused by elevated serum hepcidin levels, and this underlies the onset of functional iron-deficiency anemia. Inflammation is also inhibitory to erythropoietin function and may directly increase hepcidin level, which influences iron metabolism. Consequently, immune responses orchestrate iron metabolism, aggravate iron sequestration and, ultimately, impair the processes of erythropoiesis. Hence, functional iron-deficiency anemia is a risk factor for several ailments, disorders and diseases. Therefore, therapeutic strategies depend on the symptoms, severity, comorbidities and the associated risk factors of anemia. Oral iron supplements can be employed to treat ID and mild anemia particularly, when gastrointestinal intolerance is minimal. Intravenous (IV) iron is the option in moderate and severe anemic conditions, for patients with compromised intestinal integrity, or when oral iron is refractory. Erythropoietin (EPO) is used to treat functional iron deficiency, and blood transfusion is restricted to refractory patients or in life-threatening emergency situations. Despite these interventions, many patients remain anemic and do not respond to conventional treatment approaches. However, various novel therapies are being developed to treat persistent anemia in patients.

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“…Moreover, in this study, no statistically significant changes were observed in measures of Kidney Disease Quality of Life (KDQOL) [101,124]. This data demonstrated that Renadyl administration in uremic patients is well tolerated and safe [128].…”

Section: Probioticsmentioning

confidence: 72%

Impact of Gut Microbiota Composition on Onset and Progression of Chronic Non-Communicable Diseases

Noce¹,

Marrone

Daniele³

et al. 2019

Nutrients

116

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In recent years, mounting scientific evidence has emerged regarding the evaluation of the putative correlation between the gut microbiota composition and the presence of chronic non-communicable diseases (NCDs), such as diabetes mellitus, chronic kidney disease, and arterial hypertension. The aim of this narrative review is to examine the current literature with respect to the relationship between intestinal dysbiosis and the insurgence/progression of chronic NCDs, analyzing the physiopathological mechanisms that can induce microbiota modification in the course of these pathologies, and the possible effect induced by microbiota alteration upon disease onset. Therapy based on probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplant can represent a useful therapeutic tool, as has been highlighted on animal studies. To this moment, clinical studies that intended to demonstrate the beneficial effect induced by this kind of oral supplementation on the gut microbiota composition, and subsequent amelioration of signs and symptoms of chronic NCDs have been conducted on limited sample populations for a limited follow-up period. Therefore, to fully evaluate the therapeutic value of this kind of intervention, it would be ideal to design ample population; randomized clinical trials with a lengthy follow up period.

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Indoxyl glucuronide, a protein-bound uremic toxin, inhibits hypoxia-inducible factor‒dependent erythropoietin expression through activation of aryl hydrocarbon receptor

Cited by 25 publications

References 29 publications

Gut-Derived Protein-Bound Uremic Toxins

Gut-Derived Protein-Bound Uremic Toxins

Anemia of Inflammation with An Emphasis on Chronic Kidney Disease

Impact of Gut Microbiota Composition on Onset and Progression of Chronic Non-Communicable Diseases

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