Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo

ABSTRACT: The endocytic receptor megalin constitutes the main pathway for clearance of plasma proteins from the glomerular filtrate in the proximal tubules. However, little is know about the mechanisms that control receptor activity. A widely discussed hypothesis states that the intracellular domain (ICD) of megalin, released upon ligand binding, acts as a transcription regulator to suppress receptor expression - a mechanism proposed to safeguard the proximal tubules from protein overload. Here, we have put this hypothesis to the test by generating a mouse model co-expressing the soluble ICD and the full-length receptor. Despite pronounced expression in the proximal tubules, the ICD failed to exert any effects on renal proximal tubular function such as megalin expression, protein retrieval, or renal gene transcription. Thus, our data argue that the ICD does not play a role in regulation of megalin activity in vivo in the proximal tubules. We used microarrays to compare gene expression profile in adult kidney from a new mouse model expressing the intracellular domain of megalin with wildtype.

ORGANISM(S): Mus musculus

PROVIDER: GSE19778 | GEO | 2011/01/01

SECONDARY ACCESSION(S): PRJNA121863

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo

Project description:The endocytic receptor megalin constitutes the main pathway for clearance of plasma proteins from the glomerular filtrate in the proximal tubules. However, little is know about the mechanisms that control receptor activity. A widely discussed hypothesis states that the intracellular domain (ICD) of megalin, released upon ligand binding, acts as a transcription regulator to suppress receptor expression - a mechanism proposed to safeguard the proximal tubules from protein overload. Here, we have put this hypothesis to the test by generating a mouse model co-expressing the soluble ICD and the full-length receptor. Despite pronounced expression in the proximal tubules, the ICD failed to exert any effects on renal proximal tubular function such as megalin expression, protein retrieval, or renal gene transcription. Thus, our data argue that the ICD does not play a role in regulation of megalin activity in vivo in the proximal tubules. We used microarrays to compare gene expression profile in adult kidney from a new mouse model expressing the intracellular domain of megalin with wildtype. 10 week old mice were collected for RNA extraction and hybridization on Affymetrix microarrays. Three individuals for each genotype were analyzed comparing heterozygous animals for the intracellular domain of megalin with littermates controls.

2011-01-01 | E-GEOD-19778 | biostudies-arrayexpress

Renal Proximal Tubule Cell-specific Megalin Deletion Induces Tubulointerstitial Nephritis in Mice Fed Western Diet

Project description:Pharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), PTC-LRP2 +/+ and -/- littermates in an LDL receptor -/- background were generated and fed a Western diet to determine effects of PTC-derived megalin on atherosclerosis. PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. By contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney. Overall, PTC-specific megalin deletion leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.

2024-07-04 | GSE268879 | GEO

Spns1 controls megalin dependent endocytosis via iron misregulation

Project description:Proximal tubule endocytosis is essential for protecting the kidney from potentially damaging proteinuria and for mediating metabolic pathways, such as the activation of Vitamin D. We have identified the lysosomal membrane protein, Spns1, as a novel iron conductance that is indispensable for the normal endocytic function of the proximal tubule. Conditional knockout of Spns1 with a Cre-lox system in megalin-expressing cells in mice leads to arrest of both pinocytosis and receptor-mediated endocytosis in the proximal tubule. This endocytic defect is associated with iron overload in proximal tubules as measured by immunofluorescence of ferritin abundance and by a reduction in nascent TfRc mRNA transcripts. We have recapitulated previous findings in drosophila and zebrafish that Spns1 knockout causes endolysosomal dysfunction including abnormally enlarged lysosomes. The endocytic defect resulting from conditional Spns1 knockout can be rescued nutritionally with an iron deficient diet or genetically through double knockout of both Spns1 and the Fe2+ transporter, DMT1. Surprisingly, the endocytic defect in mice with Spns1 conditional knockout occurs despite normal megalin expression at the proximal tubule apical membrane. This data raises the possibilty that post-translational regulation of megalin activation may be nutrient-responsive.

2024-09-06 | GSE268837 | GEO

TMAO Suppresses Megalin Expression and Albumin Uptake in Human Proximal Tubular Cells Via PI3K and ERK Signaling

Project description:Trimethylamine-N-oxide (TMAO) is a uremic toxin, which has been associated with chronic kidney disease (CKD). Renal tubular epithelial cells play a central role in the pathophysiology of CKD. Megalin is an albumin-binding surface receptor on tubular epithelial cells, which is indispensable for urine protein reabsorption. To date, no studies have investigated the effect of TMAO on megalin expression and the functional properties of human tubular epithelial cells. The aim of this study was first to identify the functional effect of TMAO on human renal proximal tubular cells and second, to unravel the effects of TMAO on megalin-cubilin receptor expression. We found through global gene expression analysis that TMAO was associated with kidney disease. The microarray analysis also showed that megalin expression was suppressed by TMAO, which was also validated at the gene and protein level. High glucose and TMAO was shown to downregulate megalin expression and albumin uptake similarly. We also found that TMAO suppressed megalin expression via PI3K and ERK signaling. Furthermore, we showed that candesartan, dapagliflozin and enalaprilat counter-acted the suppressive effect of TMAO on megalin expression. Our results may further help us un-ravel the role of TMAO in CKD development and to identify new therapeutic targets to counteract TMAOs effects.

2022-08-10 | GSE210692 | GEO

Cubilin-, Megalin- and Dab2-dependent transcription revealed by CRISPR/Cas9 knockout in kidney proximal tubule cells

Project description:The multiligand receptor megalin and its endocytic adaptor protein Dab2 play essential roles in maintaining the integrity of the apical endocytic pathway of proximal tubule cells, and have complex and poorly understood roles in the development of chronic kidney disease. Here we used RNASeq in CRISPR/Cas9 knockout technology in a well-differentiated cell culture model to identify PT-specific transcriptional changes that are directly consequent to the loss of megalin (Lrp2), cubilin (Cubn), or Dab2 (Dab2) expression.

2021-12-29 | GSE176090 | GEO

Transcription profiling of gonads from E14.5 megalin+/+ and megalin-/- embryos

Project description:Presently, genes regulated by steroid hormones during induced regression of the CSL (cranial suspensory ligament) are unknown. To identify such genes and to evaluate their expression levels in megalin-deficient mice, we performed global gene expression profiling on gonads from E14.5 megalin+/+ and megalin-/- embryos.

2005-06-30 | E-MEXP-352 | biostudies-arrayexpress

Severe kidney dysfunction in sialidosis mice reveals an essential role for neuraminidase 1 in reabsorption

Project description:Sialidosis is an ultrarare multisystemic lysosomal disease caused by mutations in the neuraminidase 1 (NEU1) gene. The severe Type II form of the disease, manifests with a prenatal/infantile or juvenile onset, bone abnormalities, severe neuropathology and visceromegaly. A subset of these patients presents with nephrosialidosis, characterized by abrupt onset of fulminant glomerular nephropathy. We studied the pathophysiological mechanism of the disease in two NEU1-deficient mouse models, a constitutive Neu1 knockout Neu1ΔEx3 and a conditional phagocyte-specific knockout Neu1Cx3cr1ΔEx3. Mice of both strains exhibited terminal urinary retention and severe kidney damage with elevated urinary albumin levels, loss of nephrons, renal fibrosis, presence of storage vacuoles and dysmorphic mitochondria in the intraglomerular and tubular cells. Glycoprotein sialylation in glomeruli, proximal and distal tubules was drastically increased including that of an endocytic reabsorption receptor megalin. The pool of megalin bearing O-linked glycans with terminal galactose residues, essential for protein targeting and activity, was reduced to below detection levels. Megalin levels were severely reduced, and the protein was directed to lysosomes instead of the apical membrane. Together, our results demonstrated that desialylation by NEU1 plays a crucial role in processing and cellular trafficking of megalin and that NEU1 deficiency in sialidosis impairs megalinmediated protein reabsorption.

2024-01-26 | PXD044833 | Pride

Gene expression profiles in isolated proximal tubules and whole kidneys of rats after cisplatin-administration

Project description:To clarify the effects of cisplatin (cis-diamminedichloroplatinum II, CDDP) on the gene expression profiles in renal proximal tubules, microarray analyses were carried out using total RNA samples isolated from microdissected proximal tubules and whole kidneys. The molecular events underlying acute kidney injury (AKI) in the proximal tubules of rats with cisplatin-induced nephrotoxicity were successfully clarified with 17,000 transcripts. Renal proximal tubules were isolated under microscopy, and transcriptome data were collected with Rat Genome Survey MicroarrayÂ® (Applied Biosystems)

2013-12-24 | E-GEOD-37133 | biostudies-arrayexpress

Renal Proximal Tubule Cell-specific Megalin Deletion Induces Tubulointerstitial Nephritis in Mice Fed Western Diet

Project description:Renal Proximal Tubule Cell-specific Megalin Deletion Induces Tubulointerstitial Nephritis in Mice Fed Western Diet

| PRJNA1119377 | ENA

Peroxisomes are dispensable for normal renal function.

Project description:Peroxisomes are highly abundant in proximal tubules where peroxisomal enzymes have been proposed to play an important role in a variety of metabolic and antioxidant functions. This hypothesis was supported by human genetic studies that identified mutations leading to peroxisomal biogenesis deficiency, resulting in severe multi-organ damage (Zellweger’s spectrum disorders (ZSD)), including renal impairment. However, the role of proximal tubule peroxisomes in renal (patho)physiology remains uninvestigated. We addressed this question in mice with conditional ablation of peroxisomal biogenesis in the renal tubule. Our results demonstrate that renal tubular peroxisomes are dispensable for normal renal function and suggest that renal damage in ZSD patients is of extrarenal origin.

2022-03-02 | GSE179202 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data