Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1065405 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27561956_1.fastq.gz | Fastqsanger.gz | |||
| SRR27561956_2.fastq.gz | Fastqsanger.gz | |||
| SRR27561957_1.fastq.gz | Fastqsanger.gz | |||
| SRR27561957_2.fastq.gz | Fastqsanger.gz | |||
| SRR27561958_1.fastq.gz | Fastqsanger.gz |
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Project description:Podocyte injury is involved in the onset and progression of various kidney diseases. We previously demonstrated that the transcription factor, old astrocyte specifically induced substance (OASIS) in myofibroblasts, contributes to kidney fibrosis, as a novel role of OASIS in the kidneys. Importantly, we found that OASIS is also expressed in podocytes; however, the pathophysiological significance of OASIS in podocytes remains unknown. Upon lipopolysaccharide (LPS) treatment, there is an increase in OASIS in murine podocytes. Enhanced serum creatinine levels and tubular injury, but not albuminuria and podocyte injury, are attenuated upon podocyte-restricted OASIS knockout in LPS-treated mice, as well as diabetic mice. The protective effects of podocyte-specific OASIS deficiency on tubular injury are mediated by protein kinase C iota (PRKCI/PKCι), which is negatively regulated by OASIS in podocytes. Furthermore, podocyte-restricted OASIS transgenic mice show tubular injury and tubulointerstitial fibrosis, with severe albuminuria and podocyte degeneration. Finally, there is an increase in OASIS-positive podocytes in the glomeruli of patients with minimal change nephrotic syndrome and diabetic nephropathy. Taken together, OASIS in podocytes contributes to podocyte and/or tubular injury, in part through decreased PRKCI. The induction of OASIS in podocytes is a critical event for the disturbance of kidney homeostasis.
2022-06-22 | GSE206525 | GEO
Project description:Acute kidney injury (AKI) is in a high prevalence worldwide, but there is no therapeutic strategies nowadays. Renal tubular cell death plays a key role in the initiation and progression of AKI. However, the underlying mechanisms have not been elucidated. In this study, we found that tubular cell pyroptosis was primarily responsible to AKI progression, which is highly related with ATP depletion. FAM3A is a mitochondrial protein responsible for ATP synthesis. Herein, we found that FAM3A was decreased in AKI mice, especially in those pyroptotic tubular cells. FAM3A also decreased in clinical patients with AKI, and negatively correlated with inflammation and tubular cell injury. Gene ablation of FAM3A strongly induced NLRP3 inflammasome, Caspase-1, GSDMD, IL-1β, and IL-18, the pyroptotic markers in tubular epithelial cells, as well as triggered inflammation and mitochondrial dysfunction. Conversely, overexpression of FAM3A greatly ameliorated pyroptosis and inflammation, and reversed fatty-acid oxidation function in tubular cells. Mechanically, FAM3A activated PI3K/AKT/NRF2 pathway, which improved mitochondrial dysfunction and prevented cell pyroptosis. To activate NRF2 could strongly inhibit tubular cell pyroptosis, inflammation, mitochondrial dysfunction, and renal function decline in FAM3A knockout mice. Hence, our study provides the new mechanisms for AKI progression. We also demonstrated that FAM3A is a potential therapeutic target for treating AKI.
2025-06-01 | GSE235903 | GEO
Project description:Acute kidney injury (AKI) is a critical condition marked by a sudden decline in kidney function, often triggered by ischemia-reperfusion (IR) injury. Its pathophysiology involves inflammation, oxidative stress, and endoplasmic reticulum (ER) stress. Recently, protein tyrosine phosphatase 1B (PTP1B) has been highlighted as a therapeutic target for ischemic disease due to its potential implication in activating ER stress. In this study, we observed significant overexpression of PTP1B in human kidney tissues during AKI. Additionally, in mouse models of AKI, we confirmed that this overexpression is associated with the upregulation of ER stress and inflammatory pathways mediated by Src. To explore the effect of PTP1B inhibition in AKI, we employed PTP1B-targeting siRNA (PTPi) delivered via extracellular vesicles derived from commercial milk (mEVs). PTPi@mEVs effectively reduced PTP1B expression in proximal tubular cells, decreasing ER stress and Src kinase activation. In an IR-AKI mouse, PTPi@mEVs alleviated renal dysfunction, reduced cell death, and restored gene expression related to inflammation, ROS, and ER stress. Histological analysis confirmed that PTP1B knockdown mitigated tight junction disruption in renal tissue. These findings underscore the therapeutic potential of targeting PTP1B to mitigate AKI symptoms, highlighting the efficacy of mEVs-mediated PTPi delivery in reducing acute inflammatory responses and renal dysfunction.
2024-07-08 | GSE271279 | GEO
Project description:Acute kidney injury(AKI) is associated with an increased risk of chronic kidney disease(CKD). There is still a lack of effective prevention for AKI-CKD transition. In the present study, we simultaneously explored the contribution of GSDMD and GSDME in folic acid (FA)-induced nephropathy, a model mimicking the essential components of the AKI-CKD transition. We found that blockage of both GSDMD and GSDME-mediated pyroptosis could have accumulative protection against FA-induced AKI-CKD transition. GSDME-mediated pyroptosis played a crucial role in tubular cell damage. GSDMD could exert important functions in infiltration of inflammatory cells and NETs formation. Pyroptotic tubular cells triggered NETs generation and macrophage polarization. NETs promoted macrophage-to-myofibroblast transition. Our results illustrated the orchestration of GSDMD and GSDME in AKI-CKD transition, providing new insights into the molecular mechanism for the clinical dilemma.
2024-10-31 | GSE245446 | GEO
Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.
2023-09-18 | GSE217363 | GEO
Project description:The Hippo/YAP pathway plays a critical role in early embryonic kidney development, but its functions in the adult kidney are less well understood. Our previous work has demonstrated that tubular YAP activation induced by double knockout of the upstream Hippo kinases Mst1 and Mst2 (Mst1/2 dKO) promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Several secreted factors were found to be increased by YAP in tubular cells, but how the transcriptional network is altered by YAP is largely unknown. Here, we show that tubular YAP was already activated at 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell over-proliferation, tubular injury and renal inflammation induced by UUO or cisplatin. RNA-Seq, ChIP and luciferase assay revealed that YAP promoted the transcription of the transcription factor KLF5 whereas no interaction between YAP and KLF5 was observed. Consistently, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell over-proliferation, tubular injury and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, in which tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell over-proliferation, tubular injury and renal inflammation
2024-05-01 | GSE235443 | GEO
Project description:During kidney diseases, diverse tissue-specific pathways can regulate kidney injury and prognosis. In our study, we focused on STAT5, a member of the Janus Kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells which has been recently described in intrinsic kidney cells. STAT5 activation is detected in both human podocytes and tubular cells in FSGS and ATI, respectively. Additionally, STAT5 deficiency in either glomerular or tubular epithelium aggravates the functional and structural alterations in a range of experimental models of glomerular or tubular disease. Using RNA sequencing, we show here that STAT5b inactivation in HEK-293 cells resulted in dysregulation of multiple metabolic pathways, including glycolysis and oxidative phosphorylation. In conclusion, activating renal epithelial STAT5 represents a new therapeutic avenue with the potential for a range of beneficial effects in kidney disease.
2021-06-01 | GSE175508 | GEO
Project description:Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of its pathogenesis may lead to new therapeutic approaches. Kidney transcriptomics analyses of murine folic acid-induced AKI (FA-AKI) identified Runx1 as the most upregulated RUNX family gene. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubular cell nuclei. Bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI also upregulated kidney RUNX1. Increased tubular and interstitial RUNX1 expression were also observed in human AKI. In cultured murine tubular cells, the proinflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the Il-6 gene promoter while RUNX1 targeting with either the chemical inhibitor Ro5-3335 or a specific small interfering RNA (siRNA) prevented the TWEAK- and LPS-induced upregulation of IL-6 through a RUNX1/NFκB p50 pathway. TWEAK and LPS also induced RUNX1 binding to the promoter of Cdkn1a which encodes the cyclin-dependent kinase inhibitor p21 and increased p21 expression. In vivo, preventive Ro5-3335 improved kidney function and reduced inflammation and p21 expression in both FA-AKI, and in cytokine storm-AKI. However, administration of Ro5-3335 after the insult only improved kidney function in cytokine storm-AKI. Kidney transcriptomics identified inflammatory genes and the transcription factor Yap1 as key targets of Ro5-3335 in cytokine storm-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI.
2025-02-12 | GSE243633 | GEO
Project description:Gene expression profiling of kidneys from the murine model of HIV-associated nephropathy (HIVAN) identified an association between the expression of an endoplasmic reticulum (ER)-associated protein reticulon-1, RTN1, and the severity of kidney disease. Of the three known RTN1 isoforms, only RTN1A protein expression was increased in kidneys of murine models of HIVAN, diabetic nephropathy (DN), and renal fibrosis and humans with HIVAN and DN. Both mRNA and protein expression of RTN1-A in the kidneys correlated inversely with estimated glomerular filtration rate (eGFR) in patients with DN. In kidney cells, RTN1 overexpression induced ER stress/apoptosis, whereas RTN1 knockdown attenuated tunicamycin-, and hyperglycemia-induced ER stress/apoptosis. Incubation of kidney cells with high glucose media induced RTN1A expression likely through oxidative pathway, while knockdown of RTN1A inhibited high glucose-induced apoptosis. RTN1A interacts with PERK and mutation of its N- or C-terminal domain abolished its effects on ER stress/apoptosis. In vivo, knockdown of Rtn1a expression either before or after kidney injury attenuated renal fibrosis in mice with unilateral ureteral obstruction (UUO) and tubular epithelial cell-specific knockdown of Rtn1a also ameliorated ER stress and renal fibrosis in the UUO mice. Finally, knockdown of Rtn1a also attenuated proteinuria, glomerular hypertrophy, and mesangial expansion in STZ-induced diabetic mice, which were associated with suppression of ER stress markers. Taken together, these data suggest that RTN1 is a mediator of kidney disease progression that exacerbates kidney injury through ER stress and apoptosis.
2015-05-20 | GSE69074 | GEO
Project description:Neuropilin-1 (NRP1), a co-receptor for various cytokines, including TGF-β, has been identified as a potential therapeutic target for fibrosis. However, its role and mechanism in renal fibrosis remains elusive. Here, we show that NRP1 is upregulated in distal tubular (DT) cells of patients with transplant renal insufficiency and mice with renal ischemia-reperfusion (I-R) injury. Knockout of Nrp1 reduced multiple endpoints of renal injury and fibrosis. We found that Nrp1 facilitates the binding of TNF-α to its receptor in DT cells after renal injury. This signaling results in a downregulation of lysine crotonylation of the metabolic enzyme Cox4i1, decreased cellular energetics and exacerbation of renal injury. Furthermore, by single-cell RNA-sequencing we found that Nrp1-positive DT cells secrete collagen and communicate with myofibroblasts, exacerbating acute kidney injury (AKI)-induced renal fibrosis by activating Smad3. Dual genetic deletion of Nrp1 and Tgfbr1 in DT cells better improves renal injury and fibrosis than either single knockout. Together, these results reveal that targeting of NRP1 represents a promising strategy for the treatment of AKI and subsequent chronic kidney disease.
2024-06-03 | PXD052293 | Pride