Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression
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PROVIDER: PRJNA822123 | ENA |
REPOSITORIES: ENA
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Project description:A major obstacle in diabetes is the metabolic or hyperglycemic memory, which lacks specific therapies. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, human samples and in vitro models. Tubular and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans. Mechanistically, glucose-induced and sustained tubular p21 expression is linked to demethylation of its promoter and reduced DNMT1 expression. Exploiting signaling of the disease resolving protease activated protein C (3K3A-aPC, parmodulin-2) reversed sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence is a pathway contributing to the hyperglycemic memory, which can be therapeutically targeted.
2022-06-28 | GSE199929 | GEO
Project description:Pyruvate kinase M2 (PKM2), as the terminal and last rate-limiting enzyme of the glycolytic pathway, is an ideal enzyme for regulating metabolic phenotype. PKM2 tetramer activation has shown a protective role against diabetic kidney disease (DKD). However, the molecular mechanisms involved in diabetic tubular has not been investigated so far. In this study, we performed transcriptome gene expression profiling in human renal proximal tubular epithelial cell line (HK-2 cells) treated with high D-glucose (HG) for 7 days before the addition of 10-μM TEPP-46, an activator of PKM2 tetramerization, for a further 1 day in the presence of HG. Afterwards, we analyzed the differentially expressed (DE) genes and investigated gene relationships based on weighted gene co-expression network analysis (WGCNA). The results showed that 2,902 DE genes were identified (adjusted P-value ≤ 0.05), where 2,509 DE genes (86.46%) were co-expressed in the key module. Four extremely down-regulated DE genes (HSPA8, HSPA2, HSPA1B and ARRB1) and three extremely up-regulated DE genes (GADD45A, IGFBP3 and SIAH1) enriched in the down-regulated endocytosis (hsa04144) and up-regulated p53 signaling pathway (hsa04115), respectively, were validated by the qRT-PCR experiments. The qRT-PCR results showed that the relative expression levels of HSPA8 (adjusted P-value = 4.45×10-34 & log2(FC) = -1.12), HSPA2 (adjusted P-value = 6.09×10-14 & log2(FC) = -1.27), HSPA1B (adjusted P-value = 1.14×10-11 & log2(FC) = -1.02) and ARRB1 (adjusted P-value = 2.60×10-5 & log2(FC) = -1.13) were significantly different (P-value < 0.05) from case group to control group. Furthermore, the interactions and predicted microRNAs of the key genes (HSPA8, HSPA2, HSPA1B and ARRB1) were visualized in networks. This study identified the key candidate transcriptomic biomarkers and biological pathways in the hyperglycemic HK-2 cells responding to the PKM2 activator TEPP-46. These results will be valuable for further research on PKM2 in DKD.
2022-08-29 | GSE205674 | GEO
Project description:Hyperglycemic memory is part of the pathogenesis of diabetic retinopathy. We established a novel mouse model of intermediate-term hyperglycemic memory and demonstrated that changes in gene expression and microvascular damage in the neurovascular unit of the diabetic retina persist after euglycemic reentry, indicating memory. Using microarrays and functional annotation clustering of full genome expression data, genes meeting the criteria for hyperglycemic memory were attributed to the cytoskeletal and nuclear compartments of cells of the neurovascular unit.
2017-02-01 | GSE87433 | GEO
Project description:The cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that, through a so-far obscure mechanism, p21 could also be oncogenic. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemo-resistance. Mechanistically, sustained p21-accumulation inhibited mainly the CRL4CDT2 ubiquitin-ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery, an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.
2016-05-24 | GSE81753 | GEO
Project description:The cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that, through a so-far obscure mechanism, p21 could also be oncogenic. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemo-resistance. Mechanistically, sustained p21-accumulation inhibited mainly the CRL4CDT2 ubiquitin-ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery, an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.
2016-05-24 | GSE81752 | GEO
Project description:Epigenetic mechanisms as DNA methylation can affect allograft outcome after kidney transplantation, accelerating renal aging. Complement system is the major player of ischemia reperfusion (I/R) injury and Renal Proximal Tubular Cells (RPTEC) are known to express C5a receptor (C5aR). However, little is known about the downstream effect of C5a-C5aR interaction. We performed a whole-genome DNA methylation analysis on C5a stimulated RPTEC and found several regions regulating genes involved in cell cycle control, DNA damage checkpoints and WNT signaling. These most represented genes were BCL9, CYP1B1 and CDK6. We showed that C5a induced-aberrant gene methylation significantly influences the expression of these genes. Moreover, the stimulation of RTEC by C5a led to senescence by up-regulating SA-β Gal positivity and increasing p53 gene and p21 protein level. IL-6, MCP-1, CTGF gene levels increase indicated the tubular SASP (Senescence associated Secretory Phenotype) acquirement. In accordance, in a swine model of I/R injury, we found that the increase expression of WNT4/βcatenin expression correlated with the augment in SA-β Gal, p21, p16 and IL-6 positivity after 24h from reperfusion. The treatment with C1-INH, a complement inhibitor, efficiently antagonized SASP restoring SA-β Gal, p21, p16, IL-6 expression at basal level and abrogating the WNT4/βcatenin activation. Thus, C5a affects the DNA methylation of genes involved in tubular senescence leading to a persistent, low-grade, inflammatory state called inflammaging. Targeting epigenetic programs may offer novels strategies to protect tubular cells from aging and promote kidney repair and recovery.
2019-08-20 | GSE115227 | GEO
Project description:Dysbiosis of subgingival microbiome promotes the growth of periodontopathogens and the development of periodontitis, an irreversible chronic inflammatory disease. Untreated periodontitis leads to the destruction of connective tissues, alveolar bone resorption and ultimately to tooth loss. Periodontitis has been associated with inflammatory metabolic diseases such as type 2 diabetes. While periodontitis-induced inflammation is a key player in both, the development of subgingival microbiome dysbiosis and in the host-microbiome interaction, the effects of hyperglycemia on the regulation of the host genes controlling the inflammatory response and the host-microbiome interaction are still scarce. We investigated the impacts of a hyperglycemic microenvironment on the inflammatory response and gene expression of a gingival fibroblasts-macrophages coculture model stimulated with dysbiotic subgingival microbiomes. A coculture model composed of immortalized human gingival fibroblasts overlaid with U937 macrophages-likes cells were stimulated with subgingival microbiome collected from four healthy donors and four patients with periodontitis. Pro-inflammatory cytokines and matrix metalloproteinase were measured by a Luminex assay while the coculture RNA was submitted to a microarray analysis. Subgingival microbiomes were submitted to 16s rRNA gene sequencing. Data were analyzed by using an advanced multi-omics bioinformatic data integration model. Our results showed that krt76, krt27, pnma5, mansc4, rab41, thoc6, tm6sf2, and znf506 as well as the pro-inflammatory cytokines IL-1, GM-CSF, FGF2, IL-10, the metalloproteinases MMP3 and MMP8, and bacteria from the ASV 105, ASV 211, ASV 299, Prevotella, Campylobacter and Fretibacterium genera are key correlated variables contributing to periodontitis-induced inflammatory response in a hyperglycemic microenvironment. To conclude, our multi-omics integration analysis unveiled unique differentially interrelated bacterial genera, genes and pro-inflammatory cytokines involved in the regulation of the inflammatory response in a hyperglycemic microenvironment. These data also highlight the importance of considering hyperglycemic conditions in the development of new drugs or treatments for periodontal disease in link with type 2 diabetes.
2023-05-31 | GSE222883 | GEO
Project description:Compared with traditional manual suturing, mechanical anastomosis can reduce the error caused by human factors. The electric anastomotic device can improve the automation and accuracy of anastomosis, reduce the requirements for doctors’ operation, and establish a more standardized usage specification, thereby reducing the surgical complication rate and improving the quality of anastomosis. The clinical study of electric tubular anastomotic device adopts a multicenter, randomized, parallel controlled non-inferior study design, and randomly groups according to the 1:1 ratio to evaluate the clinical effectiveness and safety of electric tubular anastomotic device compared with conventional manual device.
| 61578 | ecrin-mdr-crc
Project description:p21 (CDKN1A) expression from an IPTG-inducible promoter in HT1080 p21-9 cells was previously shown to inhibit a set of genes, many of which are involved in cell cycle progression, and to upregulate another set of genes, some of which have been implicated in cancer and age-related diseases. We have now developed Senexin A, a small-molecule inhibitor of p21-induced transcription, which we found to be a selective inhibitor of CDK8 and CDK19. Here we tested the effect of Senexin A on the induction and inhibition of transcription by p21. In this dataset, we include microarray gene expression data from samples of HT1080 p21-9 cells that were either untreated, treated with p21-inducing IPTG alone, with Senexin A alone, or with IPTG and Senexin A. This experiment shows that Senexin A inhibits primarily the induction but not the inhibition of gene expression by p21. The data for each of the four samples were normalized to the sample from untreated cells, using GeneSpring GX. Fold changes in gene expression upon the addition of IPTG with or without Senexin A were compared using Microsft Excel. Changes in the expression of specific GO categories of genes were compared using GeneSpring.
2012-08-12 | E-GEOD-39464 | biostudies-arrayexpress
Project description:p21 (CDKN1A) expression from an IPTG-inducible promoter in HT1080 p21-9 cells was previously shown to inhibit a set of genes, many of which are involved in cell cycle progression, and to upregulate another set of genes, some of which have been implicated in cancer and age-related diseases. We have now developed Senexin A, a small-molecule inhibitor of p21-induced transcription, which we found to be a selective inhibitor of CDK8 and CDK19. Here we tested the effect of Senexin A on the induction and inhibition of transcription by p21. In this dataset, we include microarray gene expression data from samples of HT1080 p21-9 cells that were either untreated, treated with p21-inducing IPTG alone, with Senexin A alone, or with IPTG and Senexin A. This experiment shows that Senexin A inhibits primarily the induction but not the inhibition of gene expression by p21.
2012-08-13 | GSE39464 | GEO