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Analysis of proteome and phosphoproteome of mice kidney with deletion of renal tubular Raptor as compared to control animals

ABSTRACT: Raptor expression was specifically deleted in the tubular system of the kidney using an inducible Cre-Lox system under the control of a Pax8 promotor. Please see further details concerning the experimental procedures in the accompanied publication

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Kidney

DISEASE(S): Fanconi Syndrome

SUBMITTER: Markus Rinschen

LAB HEAD: Thomas Benzing

PROVIDER: PXD002422 | Pride | 2016-05-11

REPOSITORIES: Pride

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mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress

Project description:The mechanistic target of rapamycin mTORC1 is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTOR inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By utilizing constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in counter-current multiplication and urine concentration. Although mTORC2 partially compensated the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice, and caused pronounced apoptosis, diminished proliferation rates and delayed recovery. These findings identify mTORC1 as an essential regulator of tubular energy metabolism and as a crucial component of ischemic stress responses. Pharmacological inhibition of mTORC1 likely affects tubular homeostasis, and may be particularly deleterious if the kidney is exposed to acute injury. Furthermore, the combined inhibition of mTORC1 and mTORC2 may increase the susceptibility to renal damage. Raptor fl/fl*KspCre and Raptor fl/fl animals were sacrificed at P14 before the development of an overt functional phenotype. Kidneys were split in half and immediately snap frozen in liquid nitrogen.

2014-06-09 | E-GEOD-54417 | biostudies-arrayexpress

Targeted deletion of circadian clock gene Arntl in the nephron results in dysregulation of diverse metabolic pathways

Project description:The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question we performed transcriptomic analysis in mice with inducible and conditional ablation of the circadian clock system in the renal tubular cells (Bmal1lox/lox/Pax8-rtTA/LC1 mice). Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport. In parallel, kidneys from Bmal1lox/lox/Pax8-rtTA/LC1 mice exhibited a significant decrease in the NAD+/NADH ratio suggesting an increased anaerobic glycolysis and/or decreased mitochondrial function. In-depth analysis of two selected pathways revealed (i) a significant increase in plasma urea levels correlating with increased renal arginase 2 (Arg2) activity, hyperargininemia and increase of the kidney arginine content; (ii) a significantly increased plasma creatinine concentration and reduced capacity of the kidney to secrete anionic drugs (furosemide), paralleled by a ~80% decrease in the expression levels of organic anion transporter OAT3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at both the intra-renal and systemic levels and are involved in drug disposition. Mice with a specific ablation of the Arntl gene encoding BMAL1 in the renal tubular cells were compared to wild-type littermate at ZT4 and ZT16 (ZT â Zeitgeber time units; ZT0 is the time of light on and ZT12 is the time of light off).

2016-06-01 | E-GEOD-76838 | biostudies-arrayexpress

Architecture of human Rag GTPase heterodimers and their complex with mTORC1

Project description:The Rag GTPases recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-EM structure of RagA/RagC in complex with mTORC1 shows the details of RagA/C binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics show the mechanism for this locking, and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.

2019-10-11 | PXD015778 | Pride

Gene expression change in Gata2 conditional knockout mice adult renal collecting duct

Project description:We would like to know the gene expression pattern in absence of transcription factor GATA2 in adult renal collecting duct We used Gata2 flox::Pax8-rtTA::Tet-Cre to make a doxycycline induced Gata2 renal tubule cell specific knockout mice We performed microarray analyses using DBA-lectin and magnetic beads purifed collecting duct cells from WT (n=3) or Gata2 CKO mice (n=3) at 4-weeks after doxycycline induction

2013-11-19 | E-GEOD-52448 | biostudies-arrayexpress

Spectral library for targeted analysis of mouse kidney cortical collecting duct

Project description:We generated a spectral library of kidney cortical collecting ducts (CCD) using data-dependent proteomics acquisition.

2020-12-21 | PXD018795 | Pride

Transcription profiling of cortical collecting duct/connecting nephron tissue from mice treated with aldosterone, canrenoate vs. controls to identify gene products regulated by aldosterone in target cells

Project description:The mineralocorticoid hormone aldosterone controls sodium reabsorption and blood pressure largely by regulating the cell-surface expression and function of the epithelial sodium channel ENaC in target kidney tubules. Part of the stimulatory effect of aldosterone on ENaC is mediated by the induction of SGK1, a kinase that interferes with the ubiquitylation of ENaC by ubiquitin-protein ligase Nedd4-2. We performed a microarray study in order to investigate which other gene products are rapidly regulated by aldosterone in target cells that participate to the control of Na+ reabsorption and K+ secretion.

2007-03-07 | E-TABM-229 | biostudies-arrayexpress

HEK-293T LC-MS/MS

Project description:We established two in vitro cell-free systems to mimic the activation of mTORC1 and autophagy by monitoring the translocation of two readout proteins Raptor and ATG14. Based on the two systems, we further screened the potential regulators involved in the leucine-mediated mTORC1 and autophagy pathways using comparative proteomics strategy.

2022-03-03 | PXD007811 | Pride

Gene-expression changes resulting from loss of the mTORC1 component Raptor in murine hematopoietic stem and progenitor cell-enriched populations (HSPC)

Project description:We investigated the role of mTORC1 in murine hematopoiesis by conditionally deleting the Raptor gene in murine hematopoietic stem cells. We observed mutliple alterations evoked by Raptor loss in hematopoiesis and profiled gene-expression alterations induced by raptor loss in Flt3-Lin-Sca1+cKit+ hematopoietic stem and progenitor enriched cell populations, 5 weeks post Raptor deletion. Flt3-Lin-Sca1+cKit+ cells were flow sorted from mice containing homozygous floxed alleles for exon 6 of the Raptor gene in the presence (MT group) or absence (WT group) of the MxCre transgene, which was induced with injections of mice with pIpC 5 weeks before cell isolation.

2012-09-19 | E-GEOD-32265 | biostudies-arrayexpress

Targeted deletion of circadian clock gene Arntl in the nephron results in dysregulation of diverse metabolic pathways

2016-06-01 | GSE76838 | GEO

Major Action of Endogenous Lysyl Oxidase in Clear Cell Renal Cell Carcinoma Progression and Collagen Stiffness Revealed by Primary Cell Cultures

Project description:In this work we aimed to perform, for the first time in human clear cell renal cell carcinoma (ccRCC), a comprehensive and detailed study of endogenous LOX expression and functions. To overcome the difficulties and limitations due to tissue heterogeneity, we took advantage of a consolidated in vitro model of primary cell cultures that we obtained from normal kidney and ccRCC tissues. We have previously extensively characterized these primary cell cultures for their proteomic, cellular, and genomic features, and we also investigated here for their transcriptomic profile by using Affymetrix technology. This in vitro model has been instrumental for the molecular and functional analysis of endogenous LOX related to ccRCC progression.

2016-06-06 | E-MTAB-4074 | biostudies-arrayexpress

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