Erythropoietin and a hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) lowers FGF23 in a model of chronic kidney disease (CKD)

Noonan, Megan L.; Clinkenbeard, Erica L.; Ni, Pu; Swallow, Elizabeth A.; Tippen, Samantha; Agoro, Rafiou; Allen, Matthew R.; White, Kenneth E.

doi:10.14814/phy2.14434

Cited by 42 publications

(43 citation statements)

References 31 publications

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“…A recent paper, however, showed that EPO and HIF-PHI treatment of anemic mice with CKD resulted in suppressed FGF23. This study suggested that under conditions of anemia, as opposed to mice with normal iron homeostasis, rescuing iron utilization during CKD may be a more potent suppressor of FGF23 than EPO and HIF-PHIs are stimulators ( 70 ). Although EPO and HIF-PHI can induce FGF23, further studies are required to delineate the mechanisms directing these components on osteocytic FGF23 production.…”

Section: Fgf23 Production and Cleavage In Osteocytesmentioning

confidence: 98%

Osteocytic FGF23 and Its Kidney Function

Agoro

Noonan

et al. 2020

Front. Endocrinol.

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Osteocytes, which represent up to 95% of adult skeletal cells, are deeply embedded in bone. These cells exhibit important interactive abilities with other bone cells such as osteoblasts and osteoclasts to control skeletal formation and resorption. Beyond this local role, osteocytes can also influence the function of distant organs due to the presence of their sophisticated lacunocanalicular system, which connects osteocyte dendrites directly to the vasculature. Through these networks, osteocytes sense changes in circulating metabolites and respond by producing endocrine factors to control homeostasis. One critical function of osteocytes is to respond to increased blood phosphate and 1,25(OH) 2 vitamin D (1,25D) by producing fibroblast growth factor-23 (FGF23). FGF23 acts on the kidneys through partner fibroblast growth factor receptors (FGFRs) and the co-receptor Klotho to promote phosphaturia via a downregulation of phosphate transporters, as well as the control of vitamin D metabolizing enzymes to reduce blood 1,25D. In the first part of this review, we will explore the signals involved in the positive and negative regulation of FGF23 in osteocytes. In the second portion, we will bridge bone responses with the review of current knowledge on FGF23 endocrine functions in the kidneys.

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Section: Fgf23 Production and Cleavage In Osteocytesmentioning

confidence: 98%

Osteocytic FGF23 and Its Kidney Function

Agoro

Noonan

et al. 2020

Front. Endocrinol.

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“…The studies which juxtaposed the effects of roxadustat with those of erythropoietin [ 22 , 25 , 27 , 29 , 30 ] or darbapoietin [ 28 ], showed that, regarding changes in hemoglobin levels, the effects of roxadustat were not worse, while being usually better than the effects of erythropoietin…”

Section: Discussionmentioning

confidence: 99%

“…Phase 3 clinical studies of roxadustat were started in 2014. There are currently more than 15 phase 3 clinical trials underway with a target enrollment of about 10,000 patients worldwide, studying the safety, efficacy, and long-term effects of roxadustat in CKD patients, including non-dialysis-dependent [ 23 , 24 , 25 , 26 ], hemodialysis-dependent [ 22 , 25 , 27 , 28 , 29 ] and peritoneal dialysis-dependent subjects [ 25 , 30 ]. See below for a few presented examples.…”

Section: Roxadustat—phase 3 Studiesmentioning

confidence: 99%

Whether Prolyl Hydroxylase Blocker—Roxadustat—In the Treatment of Anemia in Patients with Chronic Kidney Disease Is the Future?

Grzeszczak

Szczyra

Śnit

2021

IJERPH

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In patients with chronic kidney disease (CKD), anemia develops gradually, which is primarily due to an inadequate synthesis of erythropoietin by the kidneys, as well as to iron disorders in the body, blood loss, shortened erythrocyte survival and inflammation. The currently accepted treatment employs iron, vitamin B12, folic acid supplementation and the use of erythropoiesis stimulants, which are administered only parenterally. Research is currently underway on the new erythropoiesis drugs that can be orally administered, i.e., hypoxia-inducible factor-propyl hydroxylase inhibitor (HIF-PHI) inhibitors which temporarily block propyl hydroxylase [PHD] catalysis and promote a transient increase in the expression of genes regulated by HIF, including kidney and liver erythropoietin [EPO ]. Roxadustat is the first oral drug in this class and a potent HIF-PHD inhibitor, exerted to treat anemia in patients with CKD. In phase 1, 2 and 3 studies with CKD-affected patients, roxadustat was more effective to stimulate erythropoiesis for anemia correction than previously used drugs. Roxadustat can be orally given, unlike other erythropoiesis drugs with parenteral administration only, which grants roxadustat a considerable advantage. Our paper presents the results of studies with roxadustat applied for the treatment of anemia in CKD patients with or without dialysis. We are currently not yet able to know the exact role of roxadustat in the treatment of anemia in patients with CKD, but time will tell. It is possible that roxadustat has benefits an iron metabolism and cardiovascular risk.

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“…They reported that, upon treatment with HIF-PHD inhibitor FG-4592, iFGF-23 serum levels dropped remarkably. As a result, deficiency of iron metabolism stabilized through decreased liver ferritin, Bmp6, and hepcidin mRNAs [165]. Taken together, FGF-23 constitutes an important regulator of erythropoiesis and bone homeostasis.…”

Section: Hif-epo-fgf23 Axis: Phd2/hif Inhibitionmentioning

confidence: 99%

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

Watts

Gaete

Rodríguez

et al. 2020

Preprint

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Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under deprived oxygen (hypoxia) the transcription factor Hypoxia Inducible Factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established HIF-EPO axis, and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.

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Erythropoietin and a hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) lowers FGF23 in a model of chronic kidney disease (CKD)

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 42 publications

References 31 publications

Osteocytic FGF23 and Its Kidney Function

Osteocytic FGF23 and Its Kidney Function

Whether Prolyl Hydroxylase Blocker—Roxadustat—In the Treatment of Anemia in Patients with Chronic Kidney Disease Is the Future?

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

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