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Epidermal Growth Factor Receptor Activation is Essential for Kidney Fibrosis Development

ABSTRACT: We found that EGFR expression increased in interstitial myofibroblasts in human and mouse fibrotic kidneys. Selective EGFR deletion in the fibroblast/pericyte population inhibited interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins. We used single-nucleus RNA sequencing analysis to demonstrate the role of EGFR activation in UUO model.

ORGANISM(S): Mus musculus

PROVIDER: GSE244839 | GEO | 2023/11/02

REPOSITORIES: GEO

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miR-132 mediates renal fibrosis: miRNA profiling of foxd1-derivative interstital cells derived from murine fibrotic kidneys compared to healthy kidneys

Project description:Chronic kidney disease is associated with progressive renal fibrosis, where perivascular cells give rise to the majority of Î±-SMA positive myofibroblasts. We sought to identify pericytic miRNAs that could serve as a target to decrease myofibroblast formation. We induced kidney fibrosis in FoxD1-GC;Z/Red-mice by unilateral ureteral obstruction (UUO) followed by FACS sorting of dsRed-positive FoxD1-derivative cells and miRNA profiling. MiR-132 selectively increased 21-fold during pericyte-to-myofibroblast formation whereas miR-132 was only 2.5-fold up in total kidney lysates (both in UUO and ischemia-reperfusion injury). MiR-132 silencing in UUO decreased collagen deposition (35%) and tubular apoptosis. Immunohistochemistry, western blot and qRT-PCR confirmed a similar decrease in interstitial Î±-SMA+ cells. Pathway analysis identified a rate-limiting role for miR-132 in myofibroblast proliferation that was confirmed in vitro. Indeed, antagomir-132 treated mice displayed a reduction in the number of proliferating, ki67+ interstitial myofibroblasts. Interestingly, this was selective for the interstitial compartment and did not impair the reparative proliferation of tubular epithelial cells, as evidenced by an increase in ki67+ epithelial cells, as well as increased (p-)RB1, Cyclin-A and decreased RASA1, p21 levels in kidney lysates. Taken together, silencing miR-132 counteracts the progression of renal fibrosis by selectively decreasing myofibroblast proliferation and could potentially serve as a novel antifibrotic therapy. Total RNA obtained from FACS sorted mouse FoxD1-derivative interstitial cells from healthy or fibrotic kidneys

2016-02-16 | E-GEOD-76549 | biostudies-arrayexpress

miR-132 mediates renal fibrosis: Genome-wide analysis of gene expression in foxd1-derivative interstital cells derived from fibrotic kidneys from mice treated with antagomir-132 or scramblemir

Project description:Chronic kidney disease is associated with progressive renal fibrosis, where perivascular cells give rise to the majority of Î±-SMA positive myofibroblasts. We sought to identify pericytic miRNAs that could serve as a target to decrease myofibroblast formation. We induced kidney fibrosis in FoxD1-GC;Z/Red-mice by unilateral ureteral obstruction (UUO) followed by FACS sorting of dsRed-positive FoxD1-derivative cells and miRNA profiling. MiR-132 selectively increased 21-fold during pericyte-to-myofibroblast formation whereas miR-132 was only 2.5-fold up in total kidney lysates (both in UUO and ischemia-reperfusion injury). MiR-132 silencing in UUO decreased collagen deposition (35%) and tubular apoptosis. Immunohistochemistry, western blot and qRT-PCR confirmed a similar decrease in interstitial Î±-SMA+ cells. Pathway analysis identified a rate-limiting role for miR-132 in myofibroblast proliferation that was confirmed in vitro. Indeed, antagomir-132 treated mice displayed a reduction in the number of proliferating, ki67+ interstitial myofibroblasts. Interestingly, this was selective for the interstitial compartment and did not impair the reparative proliferation of tubular epithelial cells, as evidenced by an increase in ki67+ epithelial cells, as well as increased (p-)RB1, Cyclin-A and decreased RASA1, p21 levels in kidney lysates. Taken together, silencing miR-132 counteracts the progression of renal fibrosis by selectively decreasing myofibroblast proliferation and could potentially serve as a novel antifibrotic therapy. Total RNA obtained from FACS sorted mouse renal FoxD1-derivatve interstitial cells from mice that were treated with antagomir-132 or scramblemir and underwent UUO (n=4)

2016-02-16 | E-GEOD-76548 | biostudies-arrayexpress

miR-132 mediates renal fibrosis: miRNA profiling of foxd1-derivative interstital cells derived from murine fibrotic kidneys compared to healthy kidneys

Project description:Chronic kidney disease is associated with progressive renal fibrosis, where perivascular cells give rise to the majority of α-SMA positive myofibroblasts. We sought to identify pericytic miRNAs that could serve as a target to decrease myofibroblast formation. We induced kidney fibrosis in FoxD1-GC;Z/Red-mice by unilateral ureteral obstruction (UUO) followed by FACS sorting of dsRed-positive FoxD1-derivative cells and miRNA profiling. MiR-132 selectively increased 21-fold during pericyte-to-myofibroblast formation whereas miR-132 was only 2.5-fold up in total kidney lysates (both in UUO and ischemia-reperfusion injury). MiR-132 silencing in UUO decreased collagen deposition (35%) and tubular apoptosis. Immunohistochemistry, western blot and qRT-PCR confirmed a similar decrease in interstitial α-SMA+ cells. Pathway analysis identified a rate-limiting role for miR-132 in myofibroblast proliferation that was confirmed in vitro. Indeed, antagomir-132 treated mice displayed a reduction in the number of proliferating, ki67+ interstitial myofibroblasts. Interestingly, this was selective for the interstitial compartment and did not impair the reparative proliferation of tubular epithelial cells, as evidenced by an increase in ki67+ epithelial cells, as well as increased (p-)RB1, Cyclin-A and decreased RASA1, p21 levels in kidney lysates. Taken together, silencing miR-132 counteracts the progression of renal fibrosis by selectively decreasing myofibroblast proliferation and could potentially serve as a novel antifibrotic therapy.

2016-02-16 | GSE76549 | GEO

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2016-02-16 | GSE76548 | GEO

Examining efficiency of enrichment of kidney pericyte-specific messages by TRAP (Translating Ribosome Affinity Purification)

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2014-03-01 | E-GEOD-50439 | biostudies-arrayexpress

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Project description:Gene array of kidney tissue of wild type and Notch-3 knockout mice was performed following unilateral ureteral obstruction (UUO).

2020-12-31 | GSE156181 | GEO

Microarray analysis revealed novel genes and pathways associated with neonatal unilateral ureteral obstruction

Project description:Congenital obstructive nephropathy (CON) is the leading cause of pediatric chronic kidney diseases with high morbidity and mortality.To identify differentially expressed genes, microarray analysis was performed using the unilateral ureteral obstruction (UUO)-induced neonatal rat model of CON.

2017-01-26 | E-MTAB-4984 | biostudies-arrayexpress

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Project description:Early stages of ureteral obstruction are marked by polyuria with impaired urinary concentrating ability, associated with loss of aquaporin-2 (AQP2) expression. Most mechanistic work in unilateral ureteral obstruction (UUO) models has been done at relatively late time points, making it difficult to discriminate the early effect on collecting ducts (CDs) in gene expression. Here, we use single-tubule RNA-Seq to identity signaling pathways at earlier time points after UUO in rat models.

2022-07-20 | GSE174289 | GEO

Effect of Hirudin,Curcumin or Buyang Huanwu Formulas Exposure on Gene Expression of UUO rats

Project description:We performed RNA-Seq analysis to investigate the gene expression patterns in the kidneys of rats with unilateral ureteral obstruction (UUO) treated with hirudin, curcumin or Buyang Huanwu Formula(BHF).

2021-08-06 | GSE181380 | GEO

Transcriptional profiles of kidneys that underwent reversible UUO model using model mice for erythropoietin-deficiency anemia (ISAM)

Project description:We have established a novel mouse model for postnatal erythropoietin (Epo)-deficiency anaemia, designated ISAM (inherited super anemic mouse) using a transgenic complementation rescue technique. To identify responsible signals for myofibroblastic transformation of Renal Erythropoietin-producing cells (REPs), we examined the mRNA expression profile of whole ISAM kidneys that underwent reversible UUO model. Unilateral ureteral obstruction (UUO)-induced gene expression changes were analyzed. Three UUO-treated samples (Clip), three reversed UUO kidneys (ClipR-14), and two sham-treated and one untreated samples were compared.

2013-03-20 | E-GEOD-45304 | biostudies-arrayexpress

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