Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice

Suzuki, Norio; Sasaki, Yoshiyuki; Kato, Koichiro; Yamazaki, Shun; Kurasawa, Mitsue; Yorozu, Keigo; Shimonaka, Yasushi; Yamamoto, Masayuki

doi:10.3324/haematol.2015.140814

Cited by 13 publications

(21 citation statements)

References 15 publications

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“…However, the invasiveness of subcutaneous ESA injections and the formulation costs of ESAs are problems that need to be solved (Schiller et al, 2008). Additionally, ESAs are frequently ineffective for patients suffering from chronic inflammation because EPO-dependent erythropoiesis is strongly suppressed by high serum concentrations of inflammatory cytokines and hepcidin, which negatively regulates iron usage for hemoglobin (Ganz, 2003; Smrzova et al, 2005; Suzuki et al, 2016; Petrulienė et al, 2017).…”

Section: Renal Anemiamentioning

confidence: 99%

Alteration of the DNA Methylation Signature of Renal Erythropoietin-Producing Cells Governs the Sensitivity to Drugs Targeting the Hypoxia-Response Pathway in Kidney Disease Progression

2019

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Chronic kidney disease (CKD) affects more than 10% of the population worldwide and burdens citizens with heavy medical expenses in many countries. Because a vital erythroid growth factor, erythropoietin (EPO), is secreted from renal interstitial fibroblasts [renal EPO-producing (REP) cells], anemia arises as a major complication of CKD. We determined that hypoxia-inducible factor 2α (HIF2α), which is inactivated by HIF-prolyl hydroxylase domain-containing proteins (PHDs) in an oxygen-dependent manner, tightly regulates EPO production in REP cells at the gene transcription level to maintain oxygen homeostasis. HIF2α-mediated disassembly of the nucleosome in the EPO gene is also involved in hypoxia-inducible EPO production. In renal anemia patients, anemic and pathological hypoxia is ineffective toward EPO induction due to the inappropriate over-activation of PHDs in REP cells transformed into myofibroblasts (MF-REP cells) due to kidney damage. Accordingly, PHD inhibitory compounds are being developed for the treatment of renal anemia. However, our studies have demonstrated that the promoter regions of the genes encoding EPO and HIF2α are highly methylated in MF-REP cells, and the expression of these genes is epigenetically silenced with CKD progression. This finding notably indicates that the efficacy of PHD inhibitors depends on the CKD stage of each patient. In addition, a strategy for harvesting renal cells, including REP cells from the urine of patients, is proposed to identify plausible biomarkers for CKD and to develop personalized precision medicine against CKD by a non-invasive strategy.

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Section: Renal Anemiamentioning

confidence: 99%

Alteration of the DNA Methylation Signature of Renal Erythropoietin-Producing Cells Governs the Sensitivity to Drugs Targeting the Hypoxia-Response Pathway in Kidney Disease Progression

2019

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“…C.E.R.A. (continuous Epo receptor activator also known as epoetin beta pegol or methoxy polyethylene glycol-epoetin beta, Chugai Pharmaceuticals, 3 μg/kg) was subcutaneously injected into the ISAM mice [22] . The mice were analysed 6 h after injection in the single-injection group or one week after the final injection in the 4-times-weekly injection group (Groups 6H and 28D, respectively).…”

Section: Methodsmentioning

confidence: 99%

Renal interstitial fibroblasts coproduce erythropoietin and renin under anaemic conditions

et al. 2021

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Background Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown. Methods and Findings We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure. Interpretation Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin. Funding Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.

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“…To address this issue, we further used ISAM mated with EPO-Cre (ISAM-REC) mice, whose REP cells were lineage-labeled with tdTomato. 15,17 REP cells labeled with tdTomato were also mainly positive for EPO-GFP (shown as yellow cells in Figure 7b) in BSA-injected ISAM-REC mice. Of note, the number of yellow cells was reduced by PAL-BSA injection; in place of these, tdTomato-labeled REP cells that were positive for ATF4 (shown as purple cells in Figure 7b) were observed, indicating that the ATF4 activation by palmitate in REP cells was associated with the suppression of EPO production.…”

Section: Palmitate Suppressed Epo Production In Rep Cells In the Kidnmentioning

confidence: 97%

“…All animal experiments were performed in accordance with the National Institutes of Health Guidelines for the Use and Care of Laboratory Animals and approved by the University of Tokyo Local Ethical Committee (M-P12-66) and Tohoku University (2017MdA-090). Male C57BL/6 mice (8 weeks old, body weight 20-25 g) (Nippon Bio-Supply Center, Tokyo, Japan), ISAM, or ISAM with R26T::EPO-Cre (ISAM-REC) 15,17 were i.p. injected with 0.5 ml (0.3 mg/g body weight) BSA, OLE-BSA, or PAL-BSA once daily for 11 days.…”

Section: Animal Experimentsmentioning

confidence: 99%

Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response

Anusornvongchai

Nangaku

Jao

et al. 2018

Kidney International

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Lipotoxicity plays an important role in the progression of chronic kidney damage via various mechanisms, such as endoplasmic reticulum stress. Several studies proposed renal lipotoxicity in glomerular and tubular cells but the effect of lipid on renal erythropoietin (EPO)-producing (REP) cells in the interstitium has not been elucidated. Since renal anemia is caused by derangement of EPO production in REP cells, we evaluated the effect of palmitate, a representative long-chain saturated fatty acid, on EPO production and the endoplasmic reticulum stress pathway. EPO production was suppressed by palmitate (palmitate-conjugated bovine serum albumin [BSA]) or a high palmitate diet, but not oleic acid-conjugated BSA or a high oleic acid diet, especially under cobalt-induced pseudo-hypoxia both in vitro and in vivo. Importantly, suppression of EPO production was not induced by a decrease in transcription factor HIF activity, while it was significantly associated with endoplasmic reticulum stress, particularly transcription factor ATF4 activation, which suppresses 3'-enhancer activity of the EPO gene. ATF4 knockdown by siRNA significantly attenuated the suppressive effect of palmitate on EPO production. Studies utilizing inherited super-anemic mice (ISAM) mated with EPO-Cre mice (ISAM-REC mice) for lineage-labeling of REP cells showed that ATF4 activation by palmitate suppressed EPO production in REP cells. Laser capture microdissection confirmed ATF4 activation in the interstitial area of ISAM-REC mice treated with palmitate-conjugated BSA. Thus, endoplasmic reticulum stress induced by palmitate suppressed EPO expression by REP cells in a manner independent of HIF activation. The link between endoplasmic reticulum stress, dyslipidemia, and hypoxia may contribute to development and progression of anemia in CKD.

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Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice

Cited by 13 publications

References 15 publications

Alteration of the DNA Methylation Signature of Renal Erythropoietin-Producing Cells Governs the Sensitivity to Drugs Targeting the Hypoxia-Response Pathway in Kidney Disease Progression

Alteration of the DNA Methylation Signature of Renal Erythropoietin-Producing Cells Governs the Sensitivity to Drugs Targeting the Hypoxia-Response Pathway in Kidney Disease Progression

Renal interstitial fibroblasts coproduce erythropoietin and renin under anaemic conditions

Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response

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