Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptomic analysis uncovers novel synergistic mechanisms in combination therapy for lupus nephritis

ABSTRACT: To explore the underlying molecular and cellular mechanisms of increased efficacy of the combination therapy regimen, we employed a mouse model of lupus nephritis, MRL/lpr mice, and treated them with monotherapies of prednisone, mycophenolate mofetil, or tacrolimus, or with their combination. Consistent with previous clinical findings, combination therapy markedly improved renal outcome compared to the monotherapies in mice with lupus nephritis. Transcriptomic analysis of their kidneys revealed distinct molecular pathways that were differentially regulated in combination therapy versus monotherapies. Combination therapy not only provided additive immunosuppressive effects, but also induced gene expression and molecular pathways to confer enhanced renoprotection. Specifically, combination therapy inhibited TLR7 expression in the kidneys of mice with lupus nephritis; combination of tacrolimus and mycophenolate mofetil led to better stabilization of the podocyte actin cytoskeleton through the reciprocal regulation of RhoA and Rac1 activities. Combination therapy strongly suppressed the IL-6/Stat3 pathway. These findings were further validated in renal biopsy samples from patients with lupus nephritis before and after treatments with mycophenolate mofetil, tacrolimus or combination therapy. Thus, our study further supports the earlier clinical finding and further provides insights into the molecular basis for increased efficacy of combination therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE153021 | GEO | 2020/06/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Defining molecular and cellular landscape behind non-response to Lupus Nephritis drugs

Project description:Lupus nephritis (LN) is one of the more severe systemic lupus erythematosus manifestations with the potential of developing into end stage kidney disease. Mycophenolate mofetil (MMF) and Azathioprine (AZA) are widely used for both induction and maintenance therapy for LN, but the one year complete renal response ranges from 30-40% in most trials. Reasons for non-response are still unknown. Thus, anticipating lack of drug efficacy in a patient could lead to early introduction of advanced therapies. A longitudinal cohort comprising gene-expression and clinical data of responder and non-responder samples to MMF, AZA and standar of care drugs (hidroxicloroquine (HC) and HC + glococorticoids (GC) (SOC)) was retrospectively analyzed. Response to drugs was defined over time using SRI-4 scores. Differential gene expression and functional analysis were performed. Response rate was measured based on blood cell proportions. Single-cell RNA sequencing data was analyzed to identify the cell subtypes influencing non-response and their contributing genes. SLE: Systemic Lupus Erythematosus; MMF: Mycophenolate mofetil; AZA: Azathioprine; HC: Hydroxychloroquine; PHC: Prednisone (Glucocorticoid (GC)) + HC; SOC: Standard Of Care drugs (HC and HC + PHC)

2023-05-01 | GSE224705 | GEO

Discovery of novel differentially expressed genes related to interstitial fibrosis and tubular atrophy among kidney transplantation recipients by mRNA-sequencing

Project description:Interstitial fibrosis and tubular atrophy (IF/TA) after kidney transplantation causes chronic deterioration of graft function. IF/TA can be diagnosed by graft biopsy; however, non-invasive diagnostic methods are unavailable. In this study, we identified IF/TA-related differentially expressed genes (DEGs) through next-generation sequencing using peripheral blood mononuclear cells (PBMCs) PBMC samples from kidney transplantation recipients under standard immunosuppressive therapy (tacrolimus/mycophenolate mofetil or mycophenolate sodium/steroid) and diagnosed as IF/TA (n = 41) or normal (controls; n = 41) at their 1-year protocol biopsy were recruited between January 2020 and August 2020.

2023-08-30 | GSE218048 | GEO

Global gene expression profiles in whole blood total RNA from patients with lupus nephritis, before and after initiation of therapy

Project description:Patients with systemic lupus erythematosus are characterized by the spontaneous over-expression of interferon(IFN)-induced genes in peripheral blood RNA samples. In the present study, we wanted to study the evolution of the IFN gene signature in the peripheral blood of patients with lupus nephritis, before and after initiation of immunosuppressive therapy. Strikingly, we found that immunosuppressive therapy did not strongly reduce the expression of IFN-induced genes in patients who responded to therapy, as indicated by decreased general and renal indices of disease activity. By contrast, the IFN gene signature decreased in patients developing renal failure. Global gene expression studies were performed in serial whole blood samples from SLE patients with a renal BILAG A prior to, 3 months, and 6 months after initiation of conventional immunosuppressive therapy (induction with high-dose corticosteroids, IV cyclophosphamide or oral mycophenolate during the first 3 months, followed by maintenance with moderate- to low-dose corticosteroids, azathioprine or mycophenolate). The expression of IFN-induced genes was analyzed, in comparison to global and renal indices of disease activity.

2016-02-29 | E-GEOD-72747 | 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

Human and mouse lupus nephritis cross-species transcriptional analysis

Project description:This SuperSeries is composed of the following subset Series: GSE32583: Expression data from lupus NZB/W, NZM2410, NZW/BXSB mouse kidneys prenephritic and nephritic. GSE32591: Expression data from human with lupus nephritis (LN) Refer to individual Series

2012-08-01 | E-GEOD-32592 | biostudies-arrayexpress

Kidney Transplant Rejection and Tissue Injury by Gene Profiling of Biopsies and Peripheral Blood Lymphocytes

Project description:We used DNA microarrays (HG-U95Av2 GeneChips) to determine gene expression profiles for kidney biopsies and peripheral blood lymphocytes (PBLs) in transplant patients. Sample classes include kidney biopsies and PBLs from patients with 1) healthy normal donor kidneys, 2) well-functioning transplants with no clinical evidence of rejection, 3) kidneys undergoing acute rejection, and 4) transplants with renal dysfunction without rejection. Nomenclature for samples is as follows: 1) all sample names include either BX or PBL to indicate that they were derived from biopsies or PBLs respectively, 2) C indicates samples from healthy normal donors, 3) TX indicates samples from patients with well-functioning transplants with no clinical evidence of rejection, 3) AR indicates samples from transplant patients with kidneys undergoing acute rejection, 4) NR indicates samples from transplant patients with renal dysfunction without rejection. Abbreviations used to describe patient samples include the following: BX - Biopsy; PBL- Peripheral Blood Lymphocytes; CsA -Cyclosporine; MMF - Mycophenolate Mofetil; P - Prednisone; FK - Tacrolimus; SRL - Sirolimus; CAD -Cadaveric; LD - Live Donor; Scr - Serum Creatinine; ATN - Acute Tubular Necrosis CNI - Calcineurin Inhibitor; FSGS - Focal Segmental Glomerulosclerosis several array data sets did not pass quality control and were not analyzed. These include AR1PBL, NR4BX, and NR6PBL Keywords = DNA microarrays, gene expression, kidney, rejection, transplant Keywords: other. This dataset is part of the TransQST collection.

2004-07-14 | E-GEOD-1563 | biostudies-arrayexpress

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

2008-11-21 | GSE12024 | GEO

Gene expression from microdissected glomeruli and tubulointerstitium of NZM2328 mice

Project description:To characterize molecular profiles through the development of lupus nephritis and identify risk factors for end organ damage, we carried out gene expression analysis of microdissected kidneys from lupus-prone NZM2328 mice. We identified a continuum of inflammatory processes associated with the progression from acute inflammatory to chronic destructuve disease initiated in the glomeruli and progressing to the tubulointerstitium. We examind male mice and the congenic NZM2328.R27 strain, both of which are resistant to the development of chronic nephritis and end organ damage, as a means to define pathogenic processes.

2023-07-14 | GSE206806 | GEO

Distinct pathogenic roles for resident and monocyte-derived macrophages in lupus nephritis

Project description:Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis–associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis-associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications — TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen.

2022-10-14 | GSE215272 | GEO

Mycophenolate Treatment in Systemic Sclerosis

Project description:Skin gene expression signatures, including intrinsic subset, are associated with improvement during Mycophenolate mofetil (MMF) treatment.

2014-07-25 | GSE59785 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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