Spatial transcriptomics reveals the cellular neighborhood of erythropoietin-producing cells in the mouse kidney
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE308511 | GEO | 2025/09/22
REPOSITORIES: GEO
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Project description:Anemia poses a life-threatening risk to individuals with chronic kidney diseases (CKDs). Insufficient production of erythropoietin (EPO) from injured kidney is the major reason for anemia, while lack of EPO would further aggravate the kidney injury and make a “vicious cycle”. In this study, we dissected the change of endogenous EPO signaling in injured kidney by spatial transcriptomic analysis and validated the dual beneficial effects of local recombinant EPO administration on both anemia correction and kidney protection. Next, we constructed an injury-responsive EPO producing (iREP) element to sense the kidney damage signal and drive the synthesis and secretion of native EPO. After intra-renal implantation of iREP engineered HEK-293T embryonic kidney cells, the mouse kidney would automatically produce more EPO when sensing injury signal, which in turn enhanced red blood cell mass and protected kidney from further injury. Moreover, aided with automated equipment, we cloned urine-derived SOX9+ epithelial cells (USCs) from both healthy donors or CKD patients. The USCs could be transplanted into mouse kidney and form tubule-like structures, which makes them an alternative candidate cell for iREP engineering. Altogether, the current work proposed a potential approach based on engineered “smart” cell to treat CKDs.
2025-06-01 | GSE268847 | GEO
Project description:Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production have not yet been resolved, limiting effective cell-based therapies for anemia. Here, we performed single-cell profiling of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions. We report that a distinct and homogeneous population of kidney stromal cells, which we name Norn cells, are the sole source of Epo production in vivo. Extensive characterization of the Norn epigenetic and transcriptional landscapes revealed Norn-specific markers, pathways, and transcription factor circuits conserved from mice to humans. These findings open new avenues to functionally dissect EPO gene regulation in human evolution and disease, and pave the way for the next generation of genetic and cell-based approaches for EPO therapies.
2023-03-13 | GSE193321 | GEO
Project description:As a simple lipid mediator, Lysophosphatidic acid (LPA) exerts its function by binding to 6 GPCRs (LPAR1-6) on the cell membrane. Among the 6 LPA receptors, LPAR3 is highly expressed in mouse kidney, where it has only been found to play a harmful role in kidney ischemia-reperfusion injury and diabetic nephropathy. Our previous research and other researchers found the correlation between the ATX-LPA-LPAR axis and hypoxia-related biological processes. The kidney is one of the most susceptible organs to hypoxia. It is therefore interesting to identify the function of LPAR3 in hypoxic mice kidneys. In this study, the wild-type (WT) and Lpar3-/- mice were put into a normobaric hypoxic installation and RNA sequencing analysis showed that Lpar3-/- mice showed a significant decrease in hypoxia-induced EPO expression in the kidney compared with WT mice. The impaired EPO gene expression resulted in reduced plasma EPO levels and lower hematocrit and hemoglobin levels. The KEGG enrichment analysis revealed the reduced accumulation of HIF-2α caused by LPAR3 deficiency may be the reason for insufficient hypoxic renal EPO production. In in-vitro hypoxic cell models (Hep3B cells and HK2 cells), targeting LPAR3 can also regulate HIF-2α and EPO expression. KEGG analysis revealed that the PI3K/Akt signaling pathway was involved in the regulation of LPAR3 on HIF-2α-EPO, which was validated at the tissue level and cell level. Taken together, this study demonstrates that the murine renal LPAR3 promotes HIF-2α accumulation to maintain renal EPO production by activating the downstream PI3K/Akt pathway, ensuring the generation of red blood cells in mice and plays an important role in the body's adaptation to hypoxia.
2024-11-27 | GSE264135 | GEO
Project description:Resistance to erythropoietin (EPO) treatment is observed in a considerable proportion of anemic patients with chronic kidney disease. Previous reports suggest that inflammation is one of the major independent predictors of this resistance, and pro-inflammatory cytokines have been shown to inhibit erythropoiesis. The aim of this study was to investigate EPO-induced modification to gene expression in primary cultured leukocytes. Microarray experiments were performed on ex vivo Peripheral Blood Mononuclear Cells (PBMCs) from pooled ten healthy donors (n=9), primed or not with TNF-alpha, and treated with recombinant human erythropoietin alpha (EPO-alpha). Real-time PCR experiments were used to validate expression of the molecular targets considered most relevant for inflammation. Data analysis suggested that EPO-alpha treatment mainly modulated genes involved in cell movement and cell-cell interaction in primed PBMCs. Notably, EPO-alpha exerts anti-inflammatory effects inhibiting the expression of pro-inflammatory cytokine IL-8 and its receptor CXCR2; by contrast, EPO-alpha further increases expression of genes relating to promotion of inflammation encoding for IL-1beta and CCL8, and induces de novo synthesis of IL-1alpha, CXCL1 and CXCL5 in primed PBMCs. MAPK p38alpha?reducing activity is involved in modulation of IL-1beta and IL-8 expression. In conclusion, our findings confirm the anti-inflammatory role for EPO, but also suggest a plausible in vivo scenario, in which the positive correlation found between EPO-resistance and elevated levels of some pro-inflammatory mediators is due to treatment with EPO itself. One future objective will be to perform in vivo measurement of the molecular targets highlighted, in order to identify any additional markers involved in EPO-resistance among hypo-responsive patients.
2013-12-19 | GSE53336 | GEO
Project description:Resistance to erythropoietin (EPO) treatment is observed in a considerable proportion of anemic patients with chronic kidney disease. Previous reports suggest that inflammation is one of the major independent predictors of this resistance, and pro-inflammatory cytokines have been shown to inhibit erythropoiesis. The aim of this study was to investigate EPO-induced modification to gene expression in primary cultured leukocytes. Microarray experiments were performed on ex vivo Peripheral Blood Mononuclear Cells (PBMCs) from pooled ten healthy donors (n=9), primed or not with TNF-alpha, and treated with recombinant human erythropoietin alpha (EPO-alpha). Real-time PCR experiments were used to validate expression of the molecular targets considered most relevant for inflammation. Data analysis suggested that EPO-alpha treatment mainly modulated genes involved in cell movement and cell-cell interaction in primed PBMCs. Notably, EPO-alpha exerts anti-inflammatory effects inhibiting the expression of pro-inflammatory cytokine IL-8 and its receptor CXCR2; by contrast, EPO-alpha further increases expression of genes relating to promotion of inflammation encoding for IL-1beta and CCL8, and induces de novo synthesis of IL-1alpha, CXCL1 and CXCL5 in primed PBMCs. MAPK p38alpha?reducing activity is involved in modulation of IL-1beta and IL-8 expression. In conclusion, our findings confirm the anti-inflammatory role for EPO, but also suggest a plausible in vivo scenario, in which the positive correlation found between EPO-resistance and elevated levels of some pro-inflammatory mediators is due to treatment with EPO itself. One future objective will be to perform in vivo measurement of the molecular targets highlighted, in order to identify any additional markers involved in EPO-resistance among hypo-responsive patients. In this study, we analyzed the expression profiles of pooled blood PBMCs from 10 healthy donors primed or not with TNF-alpha and then treated with EPO-alpha. All RNAs from no stimulated PBMCs were hybridized against RNAs from PBMCs treated with TNF-alpha or TNF-alpha and EPO-alpha. We performed a total of 9 technical replicates.
2013-12-19 | E-GEOD-53336 | biostudies-arrayexpress
Project description:Erythropoietin (EPO) is the major regulator of erythropoiesis, with levels increasing in response to anemia or hypoxia. Recombinant human EPO (rhEPO) is commonly used to treat anemia in patients with chronic kidney disease or cancer. Beyond its role in erythropoiesis, EPO exerts immunomodulatory effects. Emerging evidence suggests that EPO modulates other hematopoietic lineages, such as megakaryocytes while negatively impacting B-cell development. However, its influence on lympho-hematopoiesis remains insufficiently explored. We investigated the effects of EPO on B lymphopoiesis in the context of hyper-EPOemia-induced stress hematopoiesis. Using an EPO supplementation model in C57BL/6 mice, we demonstrate that EPO impairs B lymphopoiesis during Pre-Pro-B to Pro-B transition, by downregulating essential receptor like IL-7 receptor. Conversely, EPO promotes early B-cell development at the common lymphoid progenitor (CLP) and Pre-Pro-B stages. Remarkably, EPO induces the emergence of atypical B-cell precursors with a myeloid imprint, including CSF1R/CD115-expressing CLPs and CD11b and CD16/32-expressing Pre-Pro-B cells. Gene expression profiling revealed that EPO reprograms early B-cell precursors, upregulating a myeloid transcriptional signature while downregulating B-lymphoid identity genes as for instance genes targeted by key transcription factors IRF4, FOXO1, ERG and IRF8. Additionally, EPO exposure impairs hematopoietic stem and progenitor cell proliferation, induces oxidative stress and disrupts iron homeostasis. We additionally observed lymphoid over myeloid progenitor imbalance in the bone marrow and increased extramedullary hematopoiesis in the spleen. In conclusion, hyper-EPOemia reprograms B lymphopoiesis and promotes the emergence of mixed-lineage myeloid-like B cells. Future studies will explore EPO’s effects on lymphoid progenitor fate under hypoxic and infectious conditions.
2025-09-01 | GSE289311 | GEO
Project description:Background and objectives: This report describes an unusual presentation of severe hypertension (HTN) in a subset of pediatric kidney recipients treated with a steroid avoidance pediatric renal transplantation protocol. The HTN was secondary to atypical, reno-vascular abnormalities (RVA) of the transplanted vasculature, temporally associated with erythropoietin (EPO) use. Design, setting, participants, and measurements: To investigate the clinical significance underlying this event, a retrospective clinical study of 100 pediatric renal transplants was undertaken (50 steroid-free and 50 matched steroid-based controls), with peripheral blood transcriptional analysis of four RVA patients and controls. Results: Regardless of a higher observed incidence of anemia (p < 0.001) and greater overall EPO usage in the first post-transplant year in steroid-free patients, the incidence of new-onset HTN at one yr was significantly less in the steroid-free cohort (p = 0.03). Nevertheless, early EPO (first week post-transplant) was significantly associated with the combinatory findings of new-onset HTN (p = 0.03) and RVA (p = 0.007). Molecular mechanisms of RVA injury were investigated further by peripheral blood cDNA microarray gene expression profiling. A panel of 42 transcripts differentiated patients with RVA and HTN from three sets of matched controls, with and without HTN and EPO use, with 100% concordance (p < 0.001). The biological processes governed by these significant genes suggest a role for EPO regulation of growth factor receptor ubiquitination as a putative mechanism for renal vascular injury. Conclusion: This study cautions against the use early post-transplant use of EPO in immunosuppression regimens with steroid minimization/avoidance, which may have an increased incidence of post-transplant anemia. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Disease State: patient with high blood pressure Keywords: Logical Set
2008-10-21 | GSE13198 | GEO
Project description:Background and objectives: This report describes an unusual presentation of severe hypertension (HTN) in a subset of pediatric kidney recipients treated with a steroid avoidance pediatric renal transplantation protocol. The HTN was secondary to atypical, reno-vascular abnormalities (RVA) of the transplanted vasculature, temporally associated with erythropoietin (EPO) use. Design, setting, participants, and measurements: To investigate the clinical significance underlying this event, a retrospective clinical study of 100 pediatric renal transplants was undertaken (50 steroid-free and 50 matched steroid-based controls), with peripheral blood transcriptional analysis of four RVA patients and controls. Results: Regardless of a higher observed incidence of anemia (p < 0.001) and greater overall EPO usage in the first post-transplant year in steroid-free patients, the incidence of new-onset HTN at one yr was significantly less in the steroid-free cohort (p = 0.03). Nevertheless, early EPO (first week post-transplant) was significantly associated with the combinatory findings of new-onset HTN (p = 0.03) and RVA (p = 0.007). Molecular mechanisms of RVA injury were investigated further by peripheral blood cDNA microarray gene expression profiling. A panel of 42 transcripts differentiated patients with RVA and HTN from three sets of matched controls, with and without HTN and EPO use, with 100% concordance (p < 0.001). The biological processes governed by these significant genes suggest a role for EPO regulation of growth factor receptor ubiquitination as a putative mechanism for renal vascular injury. Conclusion: This study cautions against the use early post-transplant use of EPO in immunosuppression regimens with steroid minimization/avoidance, which may have an increased incidence of post-transplant anemia. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Disease State: patient with high blood pressure Keywords: Logical Set Using regression correlation
2008-10-21 | E-GEOD-13198 | biostudies-arrayexpress
Project description:Patients with combined heart and renal failure, also termed the cardiorenal syndrome (CRS), have high cardiovascular morbidity and mortality. Several key connectors between heart and kidney have been recognized, such as oxidative stress, inflammation, the renin-angiotensin system and the sympathetic nervous system. Monocytes are key players in the development of atherosclerosis and may act as a biosensor to detect changes in the systemic environment. Anemia, which occurs frequently in CRS, is partly due to an absolute and/or relative erythropoietin (EPO) deficiency. Until now, EPO treatment has largely been used to treat (renal) anemia, but recent research also showed beneficial non-hematopoietic effects such as anti-inflammatory and anti-oxidative capacities. The hypothesis of the present study was that monocyte gene expression profiles of cardiorenal patients compared to healthy controls reflect the systemic nature of CRS and are responsive to short-term treatment with Epo. The first aim was to investigate whether this short term treatment revealed non-hematopoietic EPO effects. The second aim was to address whether EPO dampens expression of genes involved in inflammation and oxidative stress. Given the variable response to EPO, the third aim was to test whether baseline gene expression profiles or the acute gene expression modulation by EPO are associated with EPO resistance.
2009-08-11 | GSE17582 | GEO
Project description:Erythropoietin (EPO) is the primary regulator of erythropoiesis in the mammalian fetus and the adult through interaction with erythropoietin receptor (EPOR). Deficiency of EPO induces anemia that is a major cause of death in patients with chronic kidney disease. Thus, development of safe treatment for anemia is an urgent issue. In this study, we investigated the effect of γ-aminobutyric acid (GABA) on serum EPO level and erythropoiesis, and its mechanism was elucidated in rat. GABA significantly (P < 0.05) increased EPO level in serum and expression levels of EPO and EPOR in a dose dependent manner. GABA increased the expression levels of HIF-1 and HIF-2 in a dose dependent manner compared with the negative control; while GABA did not affect the expression of prolyl-hydroxylase domain protein-2α (PHD-2α) gene, an oxygen sensor. GABA supplementation alters energy production pathway resulted in hypoxic condition, which increases EPO level in rat through overexpression of HIF-1 and HIF-2. This study shows a new physiological role of GABA in EPO production and thus GABA could contribute to the prevention of anemia by using alone or in combination with other anemia treating drugs.
2020-03-04 | GSE146299 | GEO