Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Renal proximal tubule cell state and metabolism are coupled by nuclear receptors

ABSTRACT: Kidney disease development is poorly understood due to the complex cellular interactions of more than 25 different cell types, each with specialized functions. Here, we used single cell RNA-sequencing to resolve cell type-specific and cell fraction changes in kidney disease. Whole kidney RNA-sequencing results were strongly influenced by cell fraction changes, but minimally informative to detect cell type-specific gene expression changes. Cell type-specific differential expression analysis identified proximal tubule cells (PT cells) as the key vulnerable cell type in diseased kidneys. Through unbiased cell trajectory analyses, we show that PT cell differentiation state is altered in disease state. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and reproducible association with PT cells state. The coupling of cell state and metabolism is established by nuclear receptors such as ESRRA that not only control cellular metabolism but also the expression of PT cell-specific genes in mice and patient samples.

ORGANISM(S): Mus musculus

PROVIDER: GSE156686 | GEO | 2020/12/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Metabolic programming drives proximal tubule differentiation and kidney dysfunction

Project description:Renal disease development is poorly understood, mostly because the kidney is made up of more than 20 different cell types, each of them with specific function and complex interaction. Here, we used single cell RNA sequencing to resolve cell-type specific and cell fraction changes

2020-11-30 | GSE152765 | GEO

Analysis of renal protective effects of ARB and SGLT2i at single cell level.

Project description:Angiotensin receptor blockade (ARB) and sodium-glucose co-transporter 2 inhibitor (SGLT2i) have been used as the standard therapy for patients with diabetic kidney disease (DKD). However, how these two drugs possess additive renal protective effects remains unclear. Here, we conducted single cell RNA-sequencing to profile the kidney cell transcriptome of db/db mice treated with vehicle, ARB, SGLT2i, or both drugs and db/m mice. We identified 10 distinct clusters of kidney cells with predominant proximal tubular (PT) cells. We found that ARB has more anti-inflammatory and anti-fibrosis effects while SGLT2i affects more mitochondrial function. We also identified a new PT subcluster which was increased in DKD but reversed by treatments.This new subcluster was also confirmed by Immunostaining of mouse and human kidneys with DKD. Together, our study reveal kidney cell-specific gene signatures in response to ARB and SGLT2i and also identified a new PT subcluster which provides new insight into DKD.

2021-11-05 | GSE181382 | GEO

Single-cell RNA sequencing of human kidney

Project description:A comprehensive cellular anatomy of normal human kidney is crucial to address the cellular origins of renal disease and renal cancer. Some kidney diseases may be cell type-specific, especially renal tubular cells. To investigate the classification and transcriptomic information of human kidney, we performed a method to obtain single-cell suspension of kidney rapidly, and conducted single-cell RNA sequencing (scRNA-seq). We present scRNA-seq data of 23,366 high quality cells from human kidneys of 3 donors. In this dataset, we show 10 clusters of normal human renal cells. Due to the high quality of single cell transcriptomic information, proximal tubule (PT) cells were classified into 3 subtypes and collecting ducts cells into 2 subtypes. Collectively, our data will provide a reliable reference for the studies of renal cell biology and kidney diseases.

2019-05-30 | GSE131685 | GEO

Loss of proximal tubular Kruppel-like factor 15 (KLF15) exacerbates kidney injury through loss of fatty acid oxidation

Project description:KLF15 has a critical role in other kidney cell types, but its role in mediating proximal tubular (PT) fatty acid oxidation (FAO) in AKI has not been determined. PT-specific KLF15 knockdown (Klf15PTKO) and control Klf15fl/fl mice were treated with multiple low doses of the PT-specific DNA-damaging agent aristolochic acid I (AAI) and RNA-sequencing of kidney cortex undertaken. Klf15PTKO exhibited worse kidney injury than Klf15fl/fl mice after AAI treatment. Immune system and integrin signaling pathways were significantly upregulated in Klf15PTKO versus Klf15fl/fl mice. Metabolic pathways, specifically FAO, were significantly downregulated in Klf15PTKO versus Klf15fl/fl mice, including PPARalpha signaling.

2023-04-28 | GSE150098 | GEO

Loss of proximal tubular Kruppel-like factor 6 (KLF6) is protective against AKI and CKD

Project description:Altered cellular metabolism in kidney proximal tubule (PT) cells plays a critical role in the development and progression of acute kidney injury (AKI). The transcription factor Krüppel-like factor 6 (KLF6) is rapidly and robustly induced in the PT after AKI, suggesting an early-inducible injury response gene. PT-specific Klf6 knockdown (Klf6PTKO) are protected from AKI and resulting fibrosis in mice. Combined RNA-sequencing and ChIP-sequencing demonstrated preserved expression of genes encoding branched chain amino acid (BCAA) catabolic enzymes in Klf6PTKO mice, with several of the genes also having KLF6 binding sites close to their transcription start sites. Conversely, inducible KLF6 overexpression suppressed expression of BCAA genes and exacerbated kidney injury and fibrosis in mice. Injured kidney cells could not respond to the BCAA catabolic activator BT2, and injured cells overexpressing KLF6 were less able to utilize BCAA. Thus, targeting KLF6-mediated suppression of BCAA catabolism may serve as key therapeutic target in AKI and kidney fibrosis.

2021-05-18 | GSE150656 | GEO

Proximal tubular transcriptional response to aristolochic acid

Project description:The proximal tubule is particularly susceptible to acute kidney injury caused by ischemic or toxic insults, due to its high oxygen demand, and role in excreting drugs such as DNA-damaging chemotherapeutics. AKI triggers PT cell de-differentiation, expression or pro-inflammatory and pro-fibrotic signaling molecules, and a dramatic shift in PT cell metabolism with severe suppression of fatty acid oxidation. The aim of this study was to investigate the transcriptional changes that occur in the S2 and S3 segments of the PT in response to the DNA damaging agent aristolochic acid I (AAI).

2021-05-18 | GSE150897 | GEO

Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney

Project description:Mammalian organs exhibit distinct physiology, disease susceptibility and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA-seq data analyses demonstrated sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors highlighted direct androgen receptor (AR) mediated regulation of gene activity in PT cells as the primary regulatory mechanism. Single-nuclear multiomic analysis identified putative cis regulatory regions and cooperating factors mediating PT responses to AR activity. In the human kidney, a limited set of genes showed conserved sex-linked regulation. Comparative analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. The organ-specific pathways of sexual differentiation identified here raise interesting questions on the evolution, physiological significance, and disease-linkage of sexually dimorphic gene activity.

2023-08-02 | GSE225566 | GEO

Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration

Project description:The kidney tubules have tremendous capacity to repair after acute injury, however, pathways guiding adaptive and maladaptive (fibrotic) repair are poorly understood. We developed a model of adaptive and maladaptive kidney regeneration by titrating ischemic injury dose. We performed detailed biochemical and histological analysis and profiled transcriptomic changes at bulk and single-cell level in >110,000 cells over time. Our analysis highlighted kidney proximal tubule (PT) cells as key susceptible cells to injury. Adaptive PT repair correlated with fatty acid oxidation and oxidative phosphorylation. We identified a specific maladaptive/profibrotic PT cluster after long ischemia. These cells expressed proinflammatory and profibrotic cytokines and myeloid cell chemotactic factor. Druggability analysis highlighted pyroptosis and ferroptosis as vulnerable pathways in these profibrotic cells. Pharmacological targeting of pyroptosis/ferroptosis in animal model, pushed cells towards adaptive repair and successfully reduced fibrosis. In summary, our single-cell analysis defined key differences in adaptive and maladaptive repair and identified druggable pathways for pharmacological intervention to prevent kidney fibrosis.

2021-07-21 | GSE180420 | GEO

Cubilin is a Novel Target Antigen in Anti-Brush Border Antibody Disease

Project description:Autoimmune diseases that affect the kidney proximal tubule (PT) cause proteinuria and are implicated in the pathogenesis of kidney failure. Previous evidence demonstrated that circulating anti-brush border antibodies (ABBA) target megalin (LRP2) but whether other components of the PT drive autoimmunity was unknown. Here we investigate a patient with LRP2-negative ABBA disease, and applied immunoprecipitation, mass spectrometry, and confocal imaging to identify cubilin as a novel antigen associated with the autoimmune disorder.

2023-04-06 | PXD030159 | Pride