Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

ABSTRACT: Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and glomerular complement deposition, which are all characteristic features of PI3K delta (PI3Kδ) inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263909 | GEO | 2024/06/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

PIK3CA as a therapeutic target for patients with proliferative glomerulonephritis

Project description:Proliferative glomerulonephritis is a severe kidney condition often associated with advanced renal failure. Unfortunately, there is a significant lack of effective treatment options for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in glomerular epithelial cells of a patient, we demonstrate using multiple genetically engineered mouse models, single cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway in proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. In addition, we show that alpelisib, a clinically approved pharmacological PI3Ka inhibitor, improves glomerular lesions and kidney function in different models of collapsing glomerulopathy and lupus nephritis by targeting podocytes. But surprisingly, we uncovered that pharmacological inhibition of PI3Ka affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and complement deposition, all of which are characteristic features of PI3Kd inhibition. These findings were further confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Ka in proliferative glomerular lesion and show for the first time that alpelisib holds promise as a therapeutic approach that acts on both, glomerular epithelial cells and immune system.

2024-07-03 | GSE264194 | GEO

Reversible SAHH inhibitor protects against glomerulonephritis in lupus-prone NZB/NZW F1 mice by modulating α-actinin-4 associated skeleton organization of podocytes

Project description:Glomerulonephritis is one of the major complications and causes of death in systemic lupus erythematosus (SLE). Podocytes can be injured in many forms of glomerular disease, characteristic changes are actin cytoskeleton reorganization of involved foot process. ACTN4, encodes α-actinin-4, an actin-binding and crosslinking protein localized to podocytes in renal glomerulus. Abnormal expression of α-actinin-4 in mice leads to proteinuria and podocyte damage. DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. Here, we found that DZ2002 could significantly ameliorate nephritis of lupus-prone mice. Our results showed that DZ2002 decreased the accumulation of α-actinin-4, inhibited expression of integrin-linked kinase and downstream phosphorylation of β1-integrin.

2019-11-12 | PXD010059 | Pride

PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

Project description:PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

| PRJNA1099900 | ENA

Nanostring Immunology V2 panel comparing expression in kidney tissue from lupus nephritis patients at diagnosis (A) and at flare (B)

Project description:The purpose of the experiment was to compare the transcriptional profile of lupus nephritis kidney tissue at a first flare and expression at a repeated lupus nephritis episode. All samples were laser microdissected into glomerular and tubular compartments and samples were ran in different cartridges. Fourteen lupus nephritis patients and ten normal controls (7 for glomeruli) FFPE samples were laser microdissected and then ran into 5 cartridges for glomeruli and 5 cartridges for tubulointerstitium. This dataset is part of the TransQST collection.

2018-04-19 | E-GEOD-113342 | biostudies-arrayexpress

Glomerular transcriptomic analysis of the influence of Genetic background effect during anti-GBM glomerulonephritis in mice

Project description:We analyzed the impact of the genetic background during experimental passive non-accelerated anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN) (an equivalent to nephrotoxic nephritis) in two different mouse genetic backgrounds (C57BL6/J vs 129S2svPAS/crl). Glomerular extracts have been made at an early time point (e.g day 4 of the induction of the glomerulonephritis). RNA have been extracted following standard procedures.

2014-07-14 | GSE56236 | GEO

Nanostring Immunology V2 panel comparing expression in kidney tissue from lupus nephritis patients at diagnosis (A) and at flare (B)

2018-04-19 | GSE113342 | GEO

NCAM1: A Novel Autoantigen in Membranous Lupus Nephritis

Project description:Membranous lupus nephritis is a frequent cause of nephrotic syndrome in patients with systemic lupus erythematosus. Unlike phospholipase A2 receptor or thrombospondin type 1 domain containing 7A-associated membranous nephropathy, where known antibodies can be detected within sera by indirect immunofluorescence and/or enzyme-linked immunosorbent assay, it is not possible to monitor disease activity in membranous lupus nephritis where the target autoantigens are mostly unknown. Determination of the target autoantigen has diagnostic significance, informs prognosis, and allows for non-invasive monitoring of disease activity in serum. We utilized mass spectrometry for antigen discovery of laser capture microdissected glomeruli from formalin-fixed paraffin embedded tissue and tissue IgG immunoprecipitation studies from frozen kidney biopsy tissue. We identified neural cell adhesion molecule 1 (NCAM1) to be a target antigen in membranous lupus nephritis and within rare cases of primary membranous nephropathy. The prevalence of NCAM1-associated membranous neuropathy was 5.7% of cases of membranous lupus nephritis. NCAM1 co-localizes with IgG within glomerular immune deposits. Additionally, serum from NCAM1 patients showed reactivity to NCAM1 recombinant protein. The presence of anti-NCAM1 antibodies in sera could allow for non-invasive monitoring of the disease. We propose that NCAM1 is a target autoantigen in a subset of patients with membranous lupus nephritis. Future studies are needed to determine whether anti-NCAM1 antibody levels correlate with disease activity or response to therapy.

2020-10-19 | PXD021123 | Pride

Tissue Transcriptome Driven Identification of Epidermal Growth Factor as a Chronic Kidney Disease Biomarker

Project description:We identified EGF as the top candidates predicting kidney function through an intrarenal transcriptome-driven approach, and demonstrated it is an independent risk predictor of CKD progression and can significantly improve prediction of renal outcome by established clinical parameters in diverse populations with CKD from a wide spectrum of causes and stages Chronic Kidney Disease, Lupus nephritis, Focal and Segmental Glomerulosclerosis, Nephropathies, Membranous Glomerulonephritis. This dataset is part of the TransQST collection.

2015-12-14 | E-GEOD-69438 | biostudies-arrayexpress

Effect of Sirolimus treatment on lupus nephritis in NZB/W F1 female mice

Project description:NZB/WF1 female mice spontaneously develop autoimmune lupus nephritis. Expression profiling of kidney tissue from (a) 12 week NZB/W F1 female mice defined as asymptomatic for lupus nephritis, (b) 36 and 42 week NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 and 42 week NZB/W F1 female mice that are diseased/symptomatic for lupus nephritis and treated with Sirolimus was carried out. The goal of the study was to identify genes associated with lupus nephritis and modulated by Sirolimus, an inhibitor of mTOR. In addition, lupus nephritis genes resistant to Sirolimus therapy were also identfied This series of samples comprises of kidney tissue from (a) 12 week old NZB/W F1 female mice defined as asymptomatic for lupus nephritis (N=4), (b) 36 (N=3) and 42 week (N=3) old NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 (N=3)and 42 (N=3) week old NZB/W F1 female mice that are asymptomatic for lupus nephritis on treatment with Sirolimus

2008-11-20 | E-GEOD-12024 | biostudies-arrayexpress

Expression data from lupus NZB/W and NZW/BXSB mouse prenephritic kidneys

Project description:We defined the shared and unique features of systemic lupus erythematosus (SLE) nephritis in 2 mouse models of proliferative renal disease. We identified shared inflammatory mechanisms of SLE nephritis that can be therapeutically targeted. Some common mechanisms are shared with non-immune-mediated renal diseases, suggesting that new strategies to prevent tissue hypoxia and remodeling may be useful in SLE nephritis.

2014-12-31 | GSE44691 | 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