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Integrative omics analyses reveal epigenetic memory in diabetic cells regulating genes associated with kidney dysfunction. [sequencing]

ABSTRACT: We report novel epigenetic mechanisms of epigenetic memory and its role in regulation of transporter genes in diabetic renal proximal tubules. We have generated RNA-seq, ATAC-seq and Infinium EPIC methylation array datasets from human primary proximal tubule epithelial cells from non-diabetic healthy controls and from patients with history of Type II Diabetes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE145746 | GEO | 2020/10/28

REPOSITORIES: GEO

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Integrative omics analyses reveal epigenetic memory in diabetic cells regulating genes associated with kidney dysfunction. [microarray]

Project description:We report novel epigenetic mechanisms of epigenetic memory and its role in regulation of transporter genes in diabetic renal proximal tubules. We have generated RNA-seq, ATAC-seq and Infinium EPIC methylation array datasets from human primary proximal tubule epithelial cells from non-diabetic healthy controls and from patients with history of Type II Diabetes. Analyses of RNA-seq, ATAC-seq and Methylaiton EPIC array data.

2020-10-28 | GSE145745 | GEO

Aberrant proximal tubule DNA methylation underlies phenotypic changes related to kidney dysfunction in patients with diabetes

Project description:Epigenetic mechanisms are considered to contribute to diabetic nephropathy by maintaining memory of poor glycemic control during the early stages of diabetes. However, DNA methylation changes in the human kidney are poorly characterized, because of the lack of cell type-specific analysis. We examined DNA methylation in proximal tubules purified from diabetic nephropathy patients and identified differentially methylated CpG sites, given the critical role of proximal tubules in the kidney injury. Hypermethylation was observed at CpG sites annotated to genes responsible for proximal tubule functions, including gluconeogenesis, nicotinamide adenine dinucleotide synthesis, transporters of glucose, water, phosphate, and drugs, in diabetic kidneys, while genes involved in oxidative stress and the cytoskeleton exhibited demethylation. Methylation levels of CpG sites annotated to ACTN1, BCAR1, MYH9, UBE4B, AFMID, TRAF2, TXNIP, FOXO3, and HNF4A were correlated with the estimated glomerular filtration rate, while methylation of the CpG site in RUNX1 was associated with interstitial fibrosis and tubular atrophy. Hypermethylation of G6PC and HNF4A was accompanied by decreased expression in diabetic kidneys. Proximal tubule-specific hypomethylation of metabolic genes related to HNF4A observed in control kidneys was compromised in diabetic kidneys, suggesting a role for aberrant DNA methylation in the dedifferentiation process. Multiple genes with aberrant DNA methylation in diabetes overlapped genes with altered expressions in maladaptive proximal tubule cells, including transcription factors PPARA and RREB1. In conclusion, DNA methylation derangement in the proximal tubules of patients with diabetes may drive phenotypic changes, characterized by inflammatory and fibrotic features, along with impaired function in metabolism and transport.

2024-07-01 | GSE233758 | GEO

Early Signaling Events in Renal Compensatory Hypertrophy Revealed by Multi-Omics

Project description:Loss of a kidney results in compensatory growth of the remaining kidney, a phenomenon of considerable clinical importance. However, the mechanisms involved are largely unknown. Here, we used a multi-omic approach in a mouse unilateral nephrectomy model to identify signaling processes associated with compensatory hypertrophy of the renal proximal tubule. Morphometry applied to microdissected proximal tubules showed that growth of the proximal tubule involves a marked, rapid increase in cell volume rather than cell number. Measurements of DNA accessibility (ATAC-seq), transcriptome (RNA-seq) and proteome (quantitative protein mass spectrometry) independently identified patterns of change that are indicative of activation of the lipid-regulated transcription factor, PPARα. Activation of PPARα by fenofibrate administration increased proximal tubule cell size, while genetic deletion of PPARα in mice decreased it. The results indicate that PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.

2023-06-05 | PXD036395 | Pride

Impact of Diabetic Stress Conditions on Renal Cell Metabolome

Project description:Diabetic kidney disease is a major complication in diabetes mellitus, and the most common reason for end-stage renal disease. Patients suffering from diabetes mellitus encounter glomerular damage by basement membrane thickening, and develop albuminuria. Subsequently, albuminuria can deteriorate the tubular function and impair the renal outcome. The impact of diabetic stress conditions on the metabolome was investigated by untargeted gas chromatography-mass spectrometry (GC-MS) analyses. The results were validated by qPCR analyses. In total, four cell lines were tested, representing the glomerulus, proximal nephron tubule, and collecting duct. Both murine and human cell lines were used. In podocytes, proximal tubular and collecting duct cells, high glucose concentrations led to global metabolic alterations in amino acid metabolism and the polyol pathway. Albumin overload led to the further activation of the latter pathway in human proximal tubular cells. In the proximal tubular cells, aldo-keto reductase was concordantly increased by glucose, and partially increased by albumin overload. Here, the combinatorial impact of two stressful agents in diabetes on the metabolome of kidney cells was investigated, revealing effects of glucose and albumin on polyol metabolism in human proximal tubular cells. This study shows the importance of including highly concentrated albumin in in vitro studies for mimicking diabetic kidney disease.

2019-10-08 | MTBLS1093 | MetaboLights

Single nucleus RNA sequencing of mosiac Pax2 and Pax8 mutant proximal tubules

Project description:Pax2 and Pax8 are homologous transcription factors required for kidney development and medullary urine concentration. However, their function in proximal tubule homeostasis and response to acute kidney injury is unknown. Mice with proximal tubules consisting of a mosaic of wild-type and Pax2/8 mutant proximal tubules cells were generated. Gene expression of mutant and wild-type proximal tubule cells was compared under homeostatic conditions using single-nucleus RNA sequencing.

2024-11-15 | GSE278289 | GEO

Transcription profiling of mouse Clcn5 knockout in proximal tubules of the kidney

Project description:Dent disease has multiple defects attributed to proximal tubule malfunction including low molecular weight proteinuria, aminoaciduria, phosphaturia and glycosuria. In order to understand the changes in kidney function of the Clc5 transporter gene knockout mouse model of Dent disease, we examined gene expression profiles from proximal tubules of mouse kidneys. Overall 720 genes are expressed differentially in the proximal tubules of the Dent Clcn5 knockout mouse model compared to those of control wild type mice. The fingerprint of these gene changes may help us to understand the phenotype of Dent disease. Experiment Overall Design: Renal proximal tubules were dissected from wild type and Clcn5 knockout mice. Mice were anesthetized with halothane, the abdominal aorta of each animal was accessed and the left kidney was perfused with an ice-cold salt. Proximal tubule dissection was performed in an ice-cold salt solution. After dissection of approximately 80-100 segments of 2 mm in length per kidney, the RNA for 3-4 mice was combined to have enough RNA per chip. Experiment Overall Design: 3 microarrays each of wild type and knockout mouse proximal tubule were processed

2008-06-11 | E-GEOD-10162 | biostudies-arrayexpress

Profiling of Transcripts in Rat Proximal Tubule

Project description:Freshly isolated rat kidney proximal tubules were subjected for transcript profiling. Three microarray experiments were done to obtain the kidney proxmial tubule transcriptome.

2009-01-26 | E-GEOD-13668 | biostudies-arrayexpress

Effect of deletion of von-Hippel-Lindau (VHL) in the proximal tubule in diabetic kidney disease

Project description:To establish the role of proximal tubular hypoxia in diabetic kidney disease, we use a mouse line with a specific deletion of von-Hippel-Lindau (VHL) in the proximal tubule and treat them with streptozotocin (STZ) to induce a type I diabetes mellitus. 10 weeks after induction of diabetes mellitus samples were collected.

2022-08-08 | GSE210401 | GEO

Proximal tubule cell maturation rate and function are controlled by PPARα signaling in kidney organoids.

Project description:Kidney organoids derived from human iPSCs have cell heterogeneity of maturation. We used single-cell RNA sequencing (scRNAs-seq) to extract the factor related to proximal tubule maturation. Using the kidney organoids cultured with the factors that accelerate the maturation speed of proximal tubules extracted by the aforementioned method, we examined whether the maturity of the proximal tubules increases within the same induction period.

2024-10-11 | GSE263556 | GEO

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Project description:Diabetes is associated with altered metabolism, but how altered metabolism contributes to the development of complications such as diabetic kidney disease is unknown. We used a systems approach with transcriptomics and mass spectrometry (MS)-based metabolomics to determine alterations in carbohydrate and lipid metabolism in kidney cortex tissue from 24-week-old BKS db/db diabetic mice and db/+ controls. Glomerular-deprived kidney cortex (kidney proximal tubule) gene expression was profiled and compared with metabolite data. Transcriptomic and metabolomic profiling demonstrated an increase in both glycolysis and fatty acid beta-oxidation,

2016-12-08 | GSE86300 | GEO

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