VCAM-1 mediates proximal tubule-immune cell cross talk in failed tubule recovery during AKI-to-CKD transition
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ABSTRACT:
PROVIDER: PRJNA1070016 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27751339_1.fastq.gz | Fastqsanger.gz | |||
| SRR27751339_2.fastq.gz | Fastqsanger.gz | |||
| SRR27751340_1.fastq.gz | Fastqsanger.gz | |||
| SRR27751340_2.fastq.gz | Fastqsanger.gz | |||
| SRR27751341_1.fastq.gz | Fastqsanger.gz |
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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:Interstitial renal inflammation contributes to the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Recently, protein lactylation modification has emerged as a novel mechanism mediating chronic organ damage. We investigated lactylated protein profiles and the role of protein lactylation during AKI progression. Severe and moderate AKI mouse models were constructed by bilateral renal ischemia for 35 and 25 min respectively. The lactylation enhancer and inhibitors were used to verify the effect of protein lactylation. Lactylated proteomics was used to detect lactylated protein changes in kidneys, and the lactylated proteins related to kidney injury were screened for verification. We observed significantly higher lactate and protein lactylation levels in the severe than in the moderate AKI model 1–28 days post-injury. Inhibition of protein lactylation protected against renal interstitial fibrosis. In vitro and in vivo experiments demonstrated that protein lactylation activated Nod-like receptor protein 3 (NLRP3) inflammasomes, promoting the AKI–CKD transition. Comprehensive lactylome profiling of severe AKI models revealed a role for lactylated proteins in metabolic pathways, primarily the tricarboxylic acid (TCA) cycle where the rate-limiting enzyme, citrate synthase (CS), exhibited significantly elevated lactylation levels 3–7 days post-AKI induction; K370 was the most significant lysine residue. In vitro, following hypoxia/reoxygenation, the modified/lactylated K370T group significantly decreased CS activity and mitochondrial function. Furthermore, CS-K370 lactylation activated the NLRP3 inflammasome. Lactylation of CS promotes the AKI–CKD transition through NLRP3 inflammasome activation. Inhibition of CS lactylation shows therapeutic potential for preventing this transition.
2025-07-07 | PXD058023 | Pride
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.
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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.
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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:Acute kidney injury (AKI) is characterized by a rapid decline in renal function. In severe or recurrent cases, AKI can progress to chronic kidney disease (CKD), marked by renal inflammation and fibrosis. Despite the severity of these outcomes, early-stage diagnostic tools and pharmacological interventions for AKI-to-CKD progression remain limited. In this study, we examined circular RNA (circRNA) expression profiles in mouse renal cortex tissues 14 days post-ischemia/reperfusion (I/R) injury using circRNA sequencing. The renal biopsy samples of patients from AKI patients exhibited reduced CircNSD1 expression, which was inversely associated with inflammation and fibrosis. Overexpression of CircNSD1 attenuated ferroptosis in vivo and in vitro, thereby slowing AKI-to-CKD progression. Mechanistically, CircNSD1 downregulated ACSL4 and SlC39A14 expression through histone H3 lysine 36 (H3K36) methylation, a critical pathway regulating ferroptosis during AKI or hypoxia/reoxygenation (H/R) injury. Furthermore, we identified that CircNSD1 encoded a NSD1-916aa peptide, which may functionally contribute to its observed effect. Collectively, these findings demonstrated that CircNSD1 may serve as a diagnostic and therapeutic target for early detection of AKI-to-CKD transition.
2025-06-22 | GSE299153 | GEO
Project description:Chronic kidney disease (CKD) is a significant global health burden. Acute kidney injury (AKI) is a risk factor for progression to CKD. Recent studies have linked a failure in proximal tubule repair as a potential contributing factor to CKD in mouse and human studies. Failed repair proximal tubule cells (FR-PTCs), initially present at the site of maximal sensitivity to ischemia reperfusion injury and spreading to more cortical regions over time, adopt a senescence-associated secretory phenotype (SASP) linked to activation of the NF-kB pathway. Several transcriptional regulatory factors mediate NF-kB pathway action. Of these, Nfkb1 is prominent within FR-PTCs and chromatin studies predict Nfkb1 interactions with pathology-associated gene targets. To examine the role of NF-kB in nephron injury outcomes, we removed Nfkb1 activity within the nephron lineage of the mouse kidney and examined the kidney’s response to bilateral ischemia reperfusion injury (Bi-IRI).
2025-06-15 | GSE294923 | GEO
Project description:Incomplete repair after acute kidney injury (AKI) is associated with progressive loss of tubular cell function and development of chronic kidney disease (CKD). Here, we compared the kidney single-cell transcriptomes from the mice subjected to either unilateral ischemia-reperfusion kidney injury with contralateral nephrectomy (IRI/CL-NX, in which tubule repair predominates) or unilateral IRI with contralateral kidney intact (U-IRI, in which fibrosis and atrophy predominates) to investigate the mechanism(s) underlying transition to CKD following AKI.
2022-06-30 | GSE197626 | 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:Background: Macrophages and tubular epithelial cell interactions are integral in kidney ischemia-incited interstitial inflammation leading to acute kidney injury (AKI). Ischemia/reperfusion injury (I/R) triggers tubular epithelial cells to express IL-34, a macrophage growth factor, that promotes AKI and subsequent CKD. IL-34 engages the cognate receptor, c-FMS, expressed by macrophages, and the recently discovered Protein-Tyrosine Phosphatase Z (Ptprz). Ptprz, binds to multiple ligands other than IL-34 that progressively increase their expression in kidneys after I/R. Methods: We tested the hypothesis that signaling through Ptprz promotes macrophage-mediated AKI and subsequent CKD, by comparing Ptprz knockout (KO) with wild-type (WT) mice after I/R. Results: Ptprz was expressed by leukocytes and in tubular epithelial cells after I/R in mice. Using Ptprz KO mice we determined that during AKI and CKD renal pathology, and loss of renal function were ameliorated. Ptprz-dependent mechanisms mediated: (i) tubular epithelial cell expression of chemokines that fostered macrophage and T cell rich renal inflammation, and (ii) tubule injury and apoptosis, that resulted in the loss of tubules and interstitial fibrosis during CKD. As macrophages release mediators that induce tubular epithelial cell apoptosis, thus Ptprz-dependent mechanisms promote tubule damage. These findings are translational, as after I/R in human kidney transplants, PTPRZ and PTPRZ ligands were upregulated and expressed by the same cell populations as in mice. Moreover, PTPRZ levels in sera were elevated in kidney transplant patients. Conclusion: Intra-renal Ptprz-dependent macrophage and tubular epithelial cell mediated mechanisms promote AKI and subsequent CKD.
2025-07-02 | GSE284133 | GEO