Mouse whole kidney, Dot1lAC vs. Dot1lf/f mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE40090 | GEO | 2013/08/14
SECONDARY ACCESSION(S): PRJNA172852
REPOSITORIES: GEO
Similar Datasets
Project description:Transcriptional profiling of whole kidneys of adult Dot1lAC mice comparing control kidneys of their littermates Dot1lf/f mice fed a normal pellet Na+ diet. Goal was to determine the effects of inactivation of histone H3 K79 methyltransferase Dot1l in Aqp2-expressing cells in Dot1lAC on global kidney gene expression. Two-condition experiment, Dot1lAC vs. Dot1lf/f. Biological replicates: Total kidney RNAs from 4 mice/genotype were mixed within the same genotype.
2013-08-14 | E-GEOD-40090 | biostudies-arrayexpress
Project description:Ubiquitylation plays an important role in the control of Na+ homeostasis by the kidney. It is well established that the epithelial Na+ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney, and is also a circadian output gene. In heterologous expression systems USP2-45 binds to ENaC, deubiquitylates it and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na+ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that the USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences to wild-type littermates with respect to the diurnal control of Na+ or K+ urinary excretion and plasma levels neither on standard diet, nor after acute and chronic changes to low and high Na+ diets, respectively. Moreover, they had similar aldosterone levels either at low or high Na+ diet. Blood pressure measurements using telemetry did not reveal variations as compared to control mice. Usp2-KO did neither display alternations in ENaC or Na+,Cl--cotransporter (NCC) expression, nor were there any changes in regulatory protein levels, as evidenced by immunoblotting and transcriptome analysis. We conclude that USP2-45 is not crucial for the regulation of Na+ balance or maintenance of blood pressure in vivo. We compared gene expression in kidneys from Usp2 Knock-Out versus Wild-Type. Six pairs of male littermates Usp2-KO and WT were combined in two pools per condition (3 animals per pool) keeping the littermate pairing between pools.
2013-01-16 | E-GEOD-43517 | biostudies-arrayexpress
Project description:Fibroblast growth factor-23 (FGF23), a circulating protein produced in bone, causes renal inorganic phosphate (Pi) wasting by down-regulation of sodium phosphate co-transporter 2a (Npt2a). The mechanism behind this action is unknown. We have previously generated transgenic mice (TG) expressing human wild-type FGF23 under the control of the α1 (I) collagen promoter. In this study we performed a large scale gene expression study of kidneys from TG mice and wild-type littermates. Several genes that play a role in Pi regulation had decreased expression levels, such as Npt2a, but also Pdzk1 which is a scaffolding protein known to interact with NPT2a. Importantly, the Klotho gene, a suggested crucial co-factor for FGF23 receptor binding and activation, was the most affected decreased gene. However, other genes proposed to regulate Pi levels, such as secreted Frizzled Related Protein 4 (sFRP4), Na+/H+ exchanger regulatory factor 1 (NHERF1) and the FGF-receptors 1-4, revealed no changes. Interestingly, expression levels of inflammatory response genes were increased and histological analysis revealed tubular nephropathy in the TG mice kidneys. In conclusion, FGF23 TG mice have altered kidney gene expression levels of several genes thought to be part of Pi homeostasis and an increase in inflammatory response genes, data supported by histological analysis. These findings may lead to further understanding of how FGF23 mediates its actions on renal Pi regulation. Experiment Overall Design: Five kidneys from FGF23 TG mice and five kidneys from WT littermates was used for Affymetrix Genechip analysis. One Genechip was used/animal. Animals were 8 weeks old when kidneys were collected.
2008-06-15 | E-GEOD-6979 | biostudies-arrayexpress
Project description:We report the nuclear Gcn5/α-KGDH complex plays vital role in histone H3 K79 succinylation. By obtaining over 731 million reads from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of histone H3 K79 succinylation, Gcn5, and α-KGDH in U251 cells.
2017-12-13 | GSE97994 | GEO
Project description:Ubiquitylation plays an important role in the control of Na+ homeostasis by the kidney. It is well established that the epithelial Na+ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney, and is also a circadian output gene. In heterologous expression systems USP2-45 binds to ENaC, deubiquitylates it and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na+ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that the USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences to wild-type littermates with respect to the diurnal control of Na+ or K+ urinary excretion and plasma levels neither on standard diet, nor after acute and chronic changes to low and high Na+ diets, respectively. Moreover, they had similar aldosterone levels either at low or high Na+ diet. Blood pressure measurements using telemetry did not reveal variations as compared to control mice. Usp2-KO did neither display alternations in ENaC or Na+,Cl--cotransporter (NCC) expression, nor were there any changes in regulatory protein levels, as evidenced by immunoblotting and transcriptome analysis. We conclude that USP2-45 is not crucial for the regulation of Na+ balance or maintenance of blood pressure in vivo.
2013-01-16 | GSE43517 | GEO
Project description:Epigenetic enzymes play critical roles in embryogenesis by defining higher-order chromatin structures required for the establishment of organ-specific transcriptional networks. In this study we investigated the role of the histone 3 lysine 79 methyltrasferase Dot1L in cardiomyocytes during development. We conducted chromatin immunoprecipitation experiments for H3K79me2 in embryonic (E16.5) and neonatal (P1) cardiomyocytes from Dot1L cardiomyocyte-specific conditional knock out and control mice. Genes that bear this modification in DOT1L controls lose it in cKOs, consistent with the model of DOT1L as the sole histone K79 methyltransferase. Overall, we identified enrichment of methylation of H3K79 in gene bodies and in regulatory regions associated wih trascription factors essential for cardiac patterning at E16.5 and with genes important for cardiomyocyte proliferation and maturation in the postnatal period.
2022-11-11 | GSE184109 | GEO
Project description:We report the application of ChIP sequencing technology for high-throughput profiling of H3K79me2 in prostate cancer cells. We generated genome-wide maps of LNCaP and PC3 cells that were treated with the specific DOT1L inhibitor EPZ004777. We find that lysine 79 dimethylation is sensitive to DOT1L inhibition in both cell lines, however the enrichment of K79 methylated peaks differed between the two cell lines.
2019-08-09 | GSE135574 | GEO
Project description:<p>Renal fibrosis, a hallmark of chronic kidney diseases, is driven by the activation of renal fibroblasts. Recent studies have highlighted the role of glycolysis in this process. Nevertheless, one critical glycolytic activator, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), remains unexplored in renal fibrosis. Upon reanalyzing the single-cell sequencing data from Dr. Humphreys' lab, we noticed an upregulation of glycolysis, gluconeogenesis, and TGFβ signaling pathway in myofibroblasts from fibrotic kidneys after unilateral ureter obstruction (UUO) or kidney ischemia/reperfusion. Furthermore, our experiments showed significant induction of PFKFB3 in mouse kidneys following UUO or kidney ischemia/reperfusion. To delve deeper into the role of PFKFB3, we generated mice with Pfkfb3 deficiency specifically in myofibroblasts (Pfkfb3f/fPostnMCM). Following UUO or kidney ischemia/reperfusion, a substantial decrease of fibrosis in injured kidneys of Pfkfb3f/fPostnMCM mice was identified compared to their wild-type littermates. Additionally, in cultured renal fibroblast NRK-49F cells, PFKFB3 was elevated upon exposure to TGFβ1, accompanied by the increase of α-SMA and fibronectin. Notably, this upregulation was significantly diminished with PFKFB3 knockdown, correlated with a glycolysis suppression. Mechanistically, the glycolytic metabolite lactate promoted the fibrotic activation of NRK-49F. In conclusion, our study demonstrates the critical role of PFKFB3 in driving fibroblast activation and subsequent renal fibrosis.</p>
2024-03-12 | MTBLS8281 | MetaboLights
Project description:The plasminogen activator inhibitor-2 (PAI-2; encoded by the SerpinB2 gene) has been described in the context of macrophage activation and in cellular senescence. As both mechanisms are important in kidney disease we tested a possible role of PAI-2 in renal injury and repair. Methods:Aging, ischemia/reperfusion injury and unilateral ureteral obstruction were performed on the mice. Bone marrow was transplantefrom SerpinB2-/- to wild-type littermates and vice versa. Primary tubular cells and macrophages from SerpinB2-/- and wildtype mice were used for functional studies and transcriptional profiling. Results: PAI-2 expression was up-regulated in cultured senescent tubular cells and in kidneys of aged mice. In the lack of PAI-2 in SerpinB2-/- mice was associated with enhanced renal fibrosis and an inflammatory phenotype during aging and in kidney injury models. While acute injury was associated with fewer monocytes/macrophages in SerpinB2-/- kidneys the subsequent resolution of inflammation seen in wildtype kidneys was lacking in knockout mice. Conclusion: PAI-2 regulates renal aging, tubular damage, and resolution of inflammation. PAI-2 is crucial for kidney repair in mice .
2019-10-22 | GSE139156 | GEO
Project description:Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby’s group and observed an increased glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3ΔMϕ) and their wild type littermates (Pfkfb3WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3ΔMϕ mice compared to Pfkfb3WT mice. This was accompanied by a substantial decrease in myeloid cell infiltration, as well as a decrease in the numbers of M1 and M2 macrophages and suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotypes that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.
2024-03-12 | MTBLS8278 | MetaboLights