Source and microenvironmental regulation of erythropoietin in the kidney

Nolan, Karen A.; Wenger, Roland H.

doi:10.1097/mnh.0000000000000420

Cited by 27 publications

(30 citation statements)

References 54 publications

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“…To assess the regulation of endogenous HIF‐dependent gene expression by the HIs, secreted Epo protein levels were analyzed in the supernatant of Hep3B cells. Epo is almost exclusively regulated at the gene expression level through HIF . All pan‐ and PHD‐selective HIs increased Epo protein levels (Figure C).…”

Section: Resultsmentioning

confidence: 99%

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HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

et al. 2019

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factor; HRB5rl, human hepatoma Hep3B cells stably transfected with the HIF-dependent Firefly luciferase reporter pH3SVL followed by the Renilla reporter construct pRL-SV40; JNJ-1935, JNJ-42041935; OTUB1, ovarian tumor domain-containing ubiquitin aldehyde binding protein 1; PHD, prolyl-4-hydroxylase domain; SDR, SensorDish Reader; SV40, simian virus 40; 2OG, 2-oxoglutarate. AbstractPharmacologic HIF hydroxylase inhibitors (HIs) are effective for the treatment of anemia in chronic kidney disease patients and may also be beneficial for the treatment of diseases such as chronic inflammation and ischemia-reperfusion injury. The selectivities of many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the translation from preclinical studies to clinical trials. We developed a novel assay that discriminates between the inhibition of HIF-α prolyl-4-hydroxylase domain (PHD) enzymes and HIF-α asparagine hydroxylase factor inhibiting HIF (FIH). We characterized 15 clinical and preclinical HIs, categorizing them into pan-HIF-α hydroxylase (broad spectrum), PHD-selective, and FIHselective inhibitors, and investigated their effects on HIF-dependent transcriptional regulation, erythropoietin production, and cellular energy metabolism. While energy homeostasis was generally maintained following HI treatment, the pan-HIs led to a stronger increase in pericellular pO 2 than the PHD/FIH-selective HIs. Combined knockdown of FIH and PHD-selective inhibition did not further increase pericellular pO 2 . Hence, the additional increase in pericellular pO 2 by pan-over PHD-selective HIs likely reflects HIF hydroxylase independent off-target effects. Overall, these analyses demonstrate that HIs can lead to oxygen redistribution within the cellular microenvironment, which should be considered as a possible contributor to HI effects in the treatment of hypoxia-associated diseases. K E Y W O R D Sanemia, hypoxia, 2-oxoglutarate oxygenase inhibitor, prolyl hydroxylase inhibitor, Roxadustat

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Section: Resultsmentioning

confidence: 99%

“…Epo is almost exclusively regulated at the gene expression level through HIF. 55 All pan-and PHD-selective HIs increased Epo protein levels ( Figure 2C). DM-NOFD treatment did not induce Epo ( Figure 2C).…”

Section: Hi Selectivity Adjusts Hif Inductionmentioning

confidence: 93%

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

et al. 2019

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“…The corticomedullary region showed the deepest drop in O 2 bioavailability, which may expand into the cortex upon decreased tissue oxygenation, a prerequisite for the recruitment of additional REP cells. 61 Our animal model allowed for the conditional tagging of acutely recruited REP cells, whereas in previously established constitutively Cre-driven REP models it remained unknown whether labeled REP cells were still active. 8,12,39,62 Wholegenome sequencing of 2 Epo-Cre ERT2 founder strains revealed that 45.9 kb 5' and 52 kb 3' flanking regions are sufficient to confer accurate tissue-specific and oxygenregulated Epo gene expression in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Generation of renal Epo-producing cell lines by conditional gene tagging reveals rapid HIF-2 driven Epo kinetics, cell autonomous feedback regulation, and a telocyte phenotype

Imeri

Nolan

Bapst

et al. 2019

Kidney International

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“…If Hgb was not measured in this period, the follow up started following the first recorded Hgb measurement after Jan 1st 2009. For incident severe CKD patients, follow up began on the date of the second measurement showing an eGFR < 30 mL/min/1.73 m 2 after Jan 1st 2009 if Hgb measurements were recorded within 1 year before that date. For these patients, anemia grade was determined based on the lowest Hgb recording during that year.…”

Section: Anemiamentioning

confidence: 99%

“…Anemia is common in patients with chronic kidney disease (CKD) and prevalence increases with CKD severity [1]. 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].…”

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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Source and microenvironmental regulation of erythropoietin in the kidney

Cited by 27 publications

References 54 publications

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

Generation of renal Epo-producing cell lines by conditional gene tagging reveals rapid HIF-2 driven Epo kinetics, cell autonomous feedback regulation, and a telocyte phenotype

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

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