Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dysregulated mesenchymal PDGFR-? drives kidney fibrosis

ABSTRACT: Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-? (PDGFR-?) positive mesenchymal cells. To study the consequences of PDGFR-ß activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-? activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch towards myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR-? activation resembled those found in patients. In conclusion, PDGFR-? activation alone is sufficient to induce progressive renal fibrosis and failure mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression.

SUBMITTER: Miriam, E. Buhl

PROVIDER: S-SCDT-EMM-2019-11021 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Dysregulated mesenchymal PDGFR-? drives kidney fibrosis.

Project description:Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-? (PDGFR-?)-positive mesenchymal cells. To study the consequences of PDGFR-? activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-? activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation, and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR-? activation resembled those found in patients. In conclusion, PDGFR-? activation alone is sufficient to induce progressive renal fibrosis and failure, mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression.

| S-EPMC7059015 | biostudies-literature

Dysregulated mesenchymal PDGFR-β drives kidney fibrosis

Project description:Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-β (PDGFR-β) positive mesenchymal cells. To study the consequences of PDGFR-ß activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch towards myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. We used microarrays to compare wildtype animals (Foxd1_wt Pdgfrb_wt) to animals with constitutive mesenchymal PDGFR-β activation (Foxd1_mt Pdgfrb V536A) in the kidney to identify target genes of PDGFR-β signaling.

2019-12-06 | GSE138819 | GEO

Dysregulated mesenchymal PDGFR-β drives kidney fibrosis

Project description:Dysregulated mesenchymal PDGFR-β drives kidney fibrosis

| PRJNA577448 | ENA

PDGFR-? and kidney fibrosis.

Project description:Chronic kidney disease (CKD) is one of the fastest growing global causes of death, estimated to rank among the top five by 2040 (Foreman et al, 2018). This illustrates current pitfalls in diagnosis and management of CKD. Advanced CKD requires renal function replacement by dialysis or transplantation. However, earlier CKD stages, even when renal function is still normal, are already associated with an increased risk of premature death (Perez-Gomez et al, 2019). Thus, novel approaches to diagnose and treat CKD are needed. The histopathological hallmark of CKD is kidney fibrosis, which is closely associated with local inflammation and loss of kidney parenchymal cells. Thus, kidney fibrosis is an attractive process to develop tests allowing an earlier diagnosis of CKD and represents a potential therapeutic target to slow CKD progression or promote regression.

| S-EPMC7059008 | biostudies-literature

PDGFR? signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity.

Project description:Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis. We show that a Nestin-Cre transgene targets perivascular cells (adventitial cells and pericyte-like cells) in WAT, and Nestin-GFP specifically labels pericyte-like cells. Activation of PDGFR? signaling in perivascular cells causes them to transition into ECM-synthesizing profibrotic cells. Before this transition occurs, PDGFR? signaling up-regulates mTOR signaling and ribosome biogenesis pathways and perturbs the expression of a network of epigenetically imprinted genes that have been implicated in cell growth and tissue homeostasis. Isolated Nestin-GFP(+) cells differentiate into adipocytes ex vivo and form WAT when transplanted into recipient mice. However, PDGFR? signaling opposes adipogenesis and generates profibrotic cells instead, which leads to fibrotic WAT in transplant experiments. These results identify perivascular cells as fibro/adipogenic progenitors in WAT and show that PDGFR? targets progenitor cell plasticity as a profibrotic mechanism.

| S-EPMC4470280 | biostudies-literature

ADAM17 substrate release in proximal tubule drives kidney fibrosis.

Project description:Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis.

| S-EPMC5026414 | biostudies-literature

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids.

Project description:Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID.

| S-EPMC8709832 | biostudies-literature

An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis.

Project description:The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.

| S-EPMC6800251 | biostudies-literature

PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease.

Project description:Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-?), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTENK27-polyUb). Genetic inhibition of PTENK27-polyUb alleviated Col4a3 knockout-, folic acid-, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTENK27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTENK27-polyUb facilitated dephosphorylation and protein stabilization of TWIST, SNAI1, and YAP in renal epithelial cells, leading to enhanced EMT. We identified that a small molecule, triptolide, inhibited MEX3C-catalyzed PTENK27-polyUb and EMT of renal epithelial cells. Treatment with triptolide reduced TWIST, SNAI1, and YAP concurrently and improved kidney health in Col4a3 knockout-, folic acid-injured disease models and STZ-induced, BTBR ob/ob diabetic nephropathy models. Hence, we demonstrated the important role of PTENK27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.

| S-EPMC6391108 | biostudies-literature

PDGFR? and ?SMA mark two distinct mesenchymal cell populations involved in parenchymal and vascular remodeling in pulmonary fibrosis.

Project description:Pulmonary fibrosis is characterized by pronounced collagen deposition and myofibroblast expansion, whose origin and plasticity remain elusive. We utilized a fate-mapping approach to investigate ?-smooth muscle actin (?SMA)+ and platelet-derived growth factor receptor ? (PDGFR?)+ cells in two lung fibrosis models, complemented by cell type-specific next-generation sequencing and investigations on human lungs. Our data revealed that ?SMA+ and PDGFR?+ cells mark two distinct mesenchymal lineages with minimal transdifferentiation potential during lung fibrotic remodeling. Parenchymal and perivascular fibrotic regions were populated predominantly with PDGFR?+ cells expressing collagen, while ?SMA+ cells in the parenchyma and vessel wall showed variable expression of collagen and the contractile protein desmin. The distinct gene expression profile found in normal conditions was retained during pathologic remodeling. Cumulatively, our findings identify ?SMA+ and PDGFR?+ cells as two separate lineages with distinct gene expression profiles in adult lungs. This cellular heterogeneity suggests that anti-fibrotic therapy should target diverse cell populations.

| S-EPMC7189793 | biostudies-literature

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