Physiology and pathophysiology of renal erythropoietin-producing cells

Shih, Hong-Mou; Wu, Chih‐Jen; Lin, Shuei-Liong

doi:10.1016/j.jfma.2018.03.017

Cited by 74 publications

(52 citation statements)

References 98 publications

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“…Renal erythropoietin-producing cells sense low tissue oxygen tension and respond by the production of erythropoietin, a hormone that stimulates red blood cell production [2]. CKD leads to a disruption of this process, erythropoietin deficiency and subsequent anemia, characterized by lower than normal number of circulating red blood cells or decreased levels of hemoglobin (Hgb) [3]. Other possible causes of anemia include blood loss, iron deficiency, inflammation and accumulation of uremic toxins [4].…”

Section: Introductionmentioning

confidence: 99%

Anemia and clinical outcomes in patients with non-dialysis dependent or dialysis dependent severe chronic kidney disease: a Danish population-based study

et al. 2019

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Background Routine clinical evidence is limited on clinical outcomes associated with anemia in patients with severe chronic kidney disease (CKD). Methods We linked population-based medical databases to identify individuals with severe CKD (eGFR < 30 mL/ min/1.73 m 2) in Northern Denmark from 2000 to 2016, including prevalent patients as of 1 January 2009 or incident patients hereafter into the study. We classified patients as non-anemic (≥ 12/≥ 13 g/dl hemoglobin (Hgb) in women/men), anemia grade 1 (10-12/13 g/dl Hgb in women/men), 2 (8-10 g/dl Hgb), and 3+ (< 8 g/dl Hgb), allowing persons to contribute with patient profiles and risk time in consecutively more severe anemia grade cohorts. Patients were stratified by dialysis status and followed for clinical outcomes. Results We identified 16,972 CKD patients contributing with a total of 28,510 anemia patient profiles, of which 3594 had dialysis dependent (DD) and 24,916 had non-dialysis dependent (NDD) severe CKD. Overall, 14% had no anemia, 35% grade 1 anemia, 44% grade 2 anemia and 17% grade 3+ anemia. Compared to patients with no anemia, adjusted hazard ratios (HRs) for NDD patients with grade 3+ anemia were elevated for incident dialysis (1.91, 95% CI 1.61-2.26), any acute hospitalization (1.74, 95% CI 1.57-1.93), all-cause death (1.82, 95% CI 1.70-1.94), and MACE (1.14, 95% CI 1.02-1.26). Similar HRs were observed among DD patients. Conclusions Among NDD or DD patients with severe CKD, presence and severity of anemia were associated with increased risks of incident dialysis for NDD patients and with acute hospitalizations, death and MACE for all patients.

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Section: Introductionmentioning

confidence: 99%

Anemia and clinical outcomes in patients with non-dialysis dependent or dialysis dependent severe chronic kidney disease: a Danish population-based study

et al. 2019

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“…The single HRE found in the LIE is crucial for maximal EPO expression and is probably bound only by HIF-2 in accordance with HIF-2 binding to enhancers [15,17,[22][23][24]. Although some candidates for the kidney-specific HRE have been identified in vitro and in vivo, no definite consensus exists [24][25][26]. Of note, HIF1A knockdown does not suppress EPO expression in the three cell lines studied so far, namely, Hep3B, Kelly, and cortical astrocytes [23,27].…”

Section: Introductionmentioning

confidence: 99%

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

Tolonen

Heikkilä

Malinen

et al. 2019

Cell. Mol. Life Sci.

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Hypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis with hundreds of hypoxiainducible target genes. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered a negative regulator of the hypoxia response pathway. However, the human HIF3A mRNA is subject to complex alternative splicing. It was recently shown that the long HIF-3α variants can form αβ dimers that possess transactivation capacity. Here, we show that overexpression of the long HIF-3α2 variant induces the expression of a subset of genes, including the erythropoietin (EPO) gene, while simultaneous downregulation of all HIF-3α variants by siRNA targeting a shared HIF3A region leads to downregulation of EPO and additional genes. EPO mRNA and protein levels correlated with HIF3A silencing and HIF-3α2 overexpression. Chromatin immunoprecipitation analyses showed that HIF-3α2 binding associated with canonical hypoxia response elements in the promoter regions of EPO. Luciferase reporter assays showed that the identified HIF-3α2 chromatin-binding regions were sufficient to promote transcription by all three HIF-α isoforms. Based on these data, HIF-3α2 is a transcription activator that directly regulates EPO expression.

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“…EPO is an acidic glycoprotein containing sialic acid whose precursor has 193 amino acids. After post-translational processing, the active protein has 165 amino acids and is highly glycosylated (19,20). The serum EPO level in healthy individuals ranges from 15 to 25 U/L (21), and the oxygenation state of tissues regulates its production.…”

Section: Epo and Related Moleculesmentioning

confidence: 99%

Advances in Understanding the Effects of Erythropoietin on Renal Fibrosis

et al. 2020

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Renal fibrosis is the common manifestation of the pathogenesis of end-stage renal disease that results from different types of renal insult, and is a hallmark of chronic kidney disease (CKD). The main pathologic characteristics of renal fibrosis are renal interstitial fibroblast hyperplasia and the aberrant and excessive deposition of extracellular matrix, pathologies that lead to the destruction of normal renal tubules and interstitial structures. However, the biological significance of fibrosis during the progression of CKD is not clear, and there are no approved clinical treatments for delaying or reversing renal fibrosis. Studies of the mechanism of renal fibrosis and of potential measures of prevention and treatment have focused on erythropoietin (EPO), a hormone best known as a regulator of red blood cell production. These recent studies have found that EPO may also provide efficient protection against renal fibrosis. Future therapeutic approaches using EPO offer new hope for patients with CKD. The aim of the present review is to briefly discuss the role of EPO in renal fibrosis, to identify its possible mechanisms in preventing renal fibrosis, and to provide novel ideas for the use of EPO in future treatments of renal fibrosis.

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Physiology and pathophysiology of renal erythropoietin-producing cells

Cited by 74 publications

References 98 publications

Anemia and clinical outcomes in patients with non-dialysis dependent or dialysis dependent severe chronic kidney disease: a Danish population-based study

Anemia and clinical outcomes in patients with non-dialysis dependent or dialysis dependent severe chronic kidney disease: a Danish population-based study

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

Advances in Understanding the Effects of Erythropoietin on Renal Fibrosis

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