Human iPSC-derived nephron progenitor cells treat AKI and CKD in mouse models
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ABSTRACT:
PROVIDER: PRJNA1228556 | ENA |
REPOSITORIES: ENA
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Project description:The number of patients requiring dialysis therapy continues to increase worldwide due to the lack of effective treatments for chronic kidney disease (CKD). Furthermore, no curative treatments for acute kidney injury (AKI) have been established. The therapeutic effects of human induced pluripotent stem cell-derived nephron progenitor cells (hiPSC-NPCs) on AKI have been reported in mice but not clinically confirmed. There are also no reports examining the therapeutic potential of hiPSC-NPCs on CKD. Although large numbers of uniform hiPSC-NPCs are required for cell therapies for AKI and CKD, effective expansion cultures remain to be developed. Here, we established a CFY (CHIR99021, FGF9, Y-27632) medium for cell culture that enables more than 100-fold proliferation of hiPSC-NPCs from multiple hiPSC lines in two passages. We demonstrated that hiPSC-NPCs expanded by CFY or their conditioned medium alone attenuate kidney injury and improve survival in cisplatin-induced AKI mice. We also observed that hiPSC-NPCs prevented kidney functional decline, interstitial fibrosis, and senescence in aristolochic acid-induced CKD mice. In addition, we discovered c-MET as a specific cell surface marker for hiPSC-NPCs and confirmed that purified c-MET+ hiPSC-NPCs have therapeutic effects on AKI and CKD. Furthermore, we found that hiPSC-NPCs exerted their therapeutic effects in AKI and CKD mice by secreting vascular endothelial growth factor A (VEGF-A). Together, expanded hiPSC-NPCs are useful cell therapies for AKI and CKD, and may open new avenues for treating kidney diseases.
2025-02-27 | GSE290520 | GEO
Project description:Macrophages are key immune cells in AKI and may determine the fate of AKI to CKD progression. Here, by taking advantages of single cell RNA-sequencing technology, we generated a mononuclear macrophage atlas from the initiation of AKI till the progression to CKD.
2024-12-31 | GSE239287 | GEO
Project description:Studies in animal models have suggested a linkage between the inflammatory response to injury and subsequent nephron loss during the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during the CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identified the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD and whole kidney RNA and protein analyses of mouse models of CKD confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Analyses of bulk RNA sequencing of TNF-α-treated primary cultured renal cells or pseudo-bulk RNA sequencing of biopsies from Kidney Precision Medicine Project datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacological inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 and TIR domain-containing adapter-inducing interferon-β suppressed TNF-α- and IL-1β-induced VCAM-1 expression in vitro. TNF-α stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the mouse proximal tubular monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD.
2024-09-03 | GSE254359 | GEO
Project description:Acute kidney injury (AKI) with maladaptive repair induces transition to chronic kidney disease (CKD) through inflammation, oxidative stress, and inappropriate homeostatic responses, including senescence and apoptosis. Here, we demonstrate that administration of cyclo Histidine-Proline (Cyclo His-Pro, CHP) protects against kidney injury and progression to CKD. Exogenous CHP pre-treatment preserved kidney function and produced significant reduction in tubular injury, apoptosis, and inflammatory cell infiltration in an ischemia-reperfusion injury (IRI) model. Compared with 5/6 nephrectomy (Nx) control rats, kidney function was protected and fibrosis was attenuated in CHP-treated 5/6 Nx rats. CHP also improved kidney injury in a unilateral ureteral obstruction (UUO) model with both prophylactic and therapeutic treatment regimens. To translate our observations to the human setting, we evaluated the relationship between endogenous CHP levels and CKD progression. As kidney function deteriorated, plasma CHP concentration increased, whereas tissue expression of Nrf2 displayed a negative relationship with CKD progression, suggesting that plasma CHP levels increase as a compensatory process to enhance the Nrf2 pathway activity. The data presented here support the efficacy of exogenous CHP treatment in preventing AKI-to-CKD transition potentially through Nrf2 pathway activation. Results: Cyclo (His-Pro) is an effective treatment for the AKI-to-CKD Transition
2025-02-08 | GSE159228 | GEO
Project description:Kidneys have a limited ability to self-repair, and their response to injury not seldomly leads to chronic kidney disease (CKD). An intriguing phenomenon of successful recovery is observed in models of unilateral acute kidney injury (AKI) upon contralateral nephrectomy. Here we aimed to better understand the cellular mechanisms of this enhanced reparative effect.In a time-course study with different nephrectomy delay times, we found that the most effective rescue after injury was observed when contralateral nephrectomy was performed early during AKI in both rats and mice. This timely intervention led to full functional recovery and attenuation of tubular atrophy, fibrosis, and inflammation, averting AKI-to-CKD transition. Morphometry of histopathology using pathomics revealed distinct trajectories of structural alterations of kidney tubules, distinguishing between atrophy and repair, as adaptive signatures. These responses were corroborated by transcriptomics analysis, which indicated improved cellular energy metabolism after nephrectomy. Lineage tracing of tubular progenitor cells showed that nephrectomy robustly stimulated their clonal expansion, surpassing the levels observed during spontaneous self-repair. Live cell cycle/DNA-content analysis of tubular cells demonstrated a robust polyploid response immediately after the ischemic insult, and revealed that nephrectomy attenuated long term tubular cell polyploidization, a contributor to CKD. Altogether, our data revealed that early timing of nephrectomy in experimental AKI induces an efficient repair response, involving tubular epithelial regeneration while counteracting the progression towards CKD.
2024-12-31 | GSE268009 | GEO
Project description:Chromatin immunoprecipitation sequencing analysis of Smad3 and EZH2 binding sites in hIPSCs and iPSC-derived nephron progenitors.
2022-12-01 | E-MTAB-10910 | biostudies-arrayexpress
Project description:<p>Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG-4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG-4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.</p><p><br></p><p>Linked study:</p><p><strong>UPLC-MS assay</strong> of mice kidney tissues sacrificed at <strong>day 21 </strong>after UIR is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3003' rel='noopener noreferrer' target='_blank'>MTBLS3003</a></p>
2021-07-22 | MTBLS3056 | MetaboLights
Project description:<p>Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG-4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG-4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.</p><p><br></p><p>Linked study:</p><p><strong>UPLC-MS assay</strong> of mice kidney tissue sacrificed at<strong> day 10 </strong>after UIR is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3056' rel='noopener noreferrer' target='_blank'>MTBLS3056</a></p>
2021-07-22 | MTBLS3003 | MetaboLights
Project description:Cyclo (His-Pro) is an effective treatment for the AKI-to-CKD Transition
| PRJNA668105 | ENA
Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.
2013-09-05 | E-GEOD-44925 | biostudies-arrayexpress