Dataset Information

Gene expression profile at bulk (24h, 48h & 72h) and single nucleus (24h) level of mouse right kidney post sham operation and unilateral nephrectomy.

ABSTRACT: The mechanism driving the remarkable ability of the remaining kidney to enlarge and increase its function following removal of its contralateral pair remains elusive. To explore the pathways driving compensatory renal hypertrophy, comprehensive RNA-seq transcriptional studies in the kidneys of mice undergoing hypertrophy 24, 48 and 72 hours following nephrectomy have been undertaken and compared with mice undergoing sham operations. The results reveal substantial time dependent enhancement of cholesterol biosynthesis pathways, increases in mitochondrial gene expression and cell cycle perturbations. Single nuclei RNA-Seq 24 hours post nephrectomy was used to further explore cholesterol biosynthesis signature and its driver SREBP2. In a cell specific manner, snRNA-seq demonstrated that SREBP2 activity increases in proximal tubules and medullary thick ascending limb and is responsible for cell size regulation following IGF-1 stimulation. These results suggest a previously undescribed role for SREBP2 in the mechanism underlying compensatory renal hypertrophy. This mechanism might be amenable to therapeutic manipulation to enhance kidney size and function.

ORGANISM(S): Mus musculus

PROVIDER: GSE241213 | GEO | 2024/07/18

REPOSITORIES: GEO

ACCESS DATA

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Project description:Immunometabolism is a growing field that centers on a core paradigm: perturbations in metabolism alter a cell’s biological response in immunity and, likewise, inflammatory signals, such as cytokines and pathogens, can directly influence cellular metabolism. Although the carbons within cholesterol cannot be used for catabolic energy production, there is a growing appreciation that a similar relationship exists between cholesterol homeostasis and immunity. The majority of this literature is focused on cholesterol dynamics in the context of leukocyte immunobiology. However, the endothelium also plays an important role during the acute inflammatory response. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury. Dysregulation or aberrant activation of ECs leads to disease, such as atherosclerosis. I studied the role of cholesterol and its master regulator, SREBP2, in the EC response to acute inflammatory stress. ECs treated with cytokines upregulated SREBP2 cleavage and classical cholesterol biosynthesis gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-kB DNA binding and classical SCAP-SREBP2 processing. We used bacterial cytolysin probes to show that inflammatory stress significantly decreased accessible cholesterol, leading to dysfunctional sterol sensing and downstream SREBP2 cleavage. We also explored what role SREBP2 plays in the EC inflammatory response. Loss of SREBP2 in ECs treated with inflammatory cytokine altered EC phenotype, which was defined by decreased chemokine expression and increased type I inflammatory signaling. Interestingly, this effect on the EC inflammatory transcriptome could not be accounted by changes in cholesterol, but rather through SREBP2 binding to promoters of pro-inflammatory transcription factors. Preliminary results revealed that BHLHE40 and KLF6 are direct targets of SREBP2 and that loss of one of KLF6 could mimic the effect of SREBP2 knockdown on chemokine expression. This study is the first to provide an in-depth characterization of the relationship between SREBP2 and the endothelial acute inflammatory response.