Novel targets in renal fibrosis based on bioinformatic analysis I
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE217650 | GEO | 2023/01/06
REPOSITORIES: GEO
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Project description:Renal fibrosis is a widely used pathological indicator of progressive chronic kidney disease (CKD), and renal fibrosis mediates most progressive renal diseases as a final pathway. Nevertheless, the key genes related to the host response are still unclear. In this study, the potential gene network, signaling pathways, and key genes under UUO model in mouse kidneys were investigated by integrating two transcriptional data profiles.
2023-01-06 | GSE217654 | GEO
Project description:Renal tubular atrophy and interstitial fibrosis are common hallmarks of etiologically different progressive chronic kidney diseases (CKD) that eventually result in organ failure. We identify Dickkopf-3 (Dkk3) as a stress-induced, tubular epithelia-derived mediator of kidney fibrosis. Genetic as well as antibody-mediated abrogation of Dkk3 led to reduced tubular atrophy and decreased interstitial matrix accumulation in two mouse models of renal fibrosis. This was accompanied by an amplified, anti-fibrogenic, inflammatory response within the injured kidney. Mechanistically, Dkk3 deficiency led to diminished canonical Wnt/β-catenin signaling in stressed tubular epithelial cells. To identify global changes in gene expression due to the lack of Dkk3, whole-transcriptome sequencing (mRNA-seq) was performed on RNA isolated from kidneys of Wt and Dkk3-/- mice 7 days after UUO.
2016-01-20 | GSE75925 | GEO
Project description:<p>Renal fibrosis, a hallmark of chronic kidney diseases, is driven by the activation of renal fibroblasts. Recent studies have highlighted the role of glycolysis in this process. Nevertheless, one critical glycolytic activator, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), remains unexplored in renal fibrosis. Upon reanalyzing the single-cell sequencing data from Dr. Humphreys' lab, we noticed an upregulation of glycolysis, gluconeogenesis, and TGFβ signaling pathway in myofibroblasts from fibrotic kidneys after unilateral ureter obstruction (UUO) or kidney ischemia/reperfusion. Furthermore, our experiments showed significant induction of PFKFB3 in mouse kidneys following UUO or kidney ischemia/reperfusion. To delve deeper into the role of PFKFB3, we generated mice with Pfkfb3 deficiency specifically in myofibroblasts (Pfkfb3f/fPostnMCM). Following UUO or kidney ischemia/reperfusion, a substantial decrease of fibrosis in injured kidneys of Pfkfb3f/fPostnMCM mice was identified compared to their wild-type littermates. Additionally, in cultured renal fibroblast NRK-49F cells, PFKFB3 was elevated upon exposure to TGFβ1, accompanied by the increase of α-SMA and fibronectin. Notably, this upregulation was significantly diminished with PFKFB3 knockdown, correlated with a glycolysis suppression. Mechanistically, the glycolytic metabolite lactate promoted the fibrotic activation of NRK-49F. In conclusion, our study demonstrates the critical role of PFKFB3 in driving fibroblast activation and subsequent renal fibrosis.</p>
2024-03-12 | MTBLS8281 | MetaboLights
Project description:In chronic kidney disease (CKD) and with ageing, individuals lose regenerative capacity after renal injury and are predisposed to progressive fibrosis and cardiovascular disease. With ageing and CKD increased numbers of activated leukocytes are present in the circulation and within the kidney where they correlate with progressive fibrosis. The potential role of activated leukocytes in mediating progressive renal and systemic fibrosis remains incompletely understood. Here, we show that tumour necrosis factor alpha (TNFa) released with injury and aging promotes renal and cardiac fibrosis. We identify a Ubiquitin D expressing population of TNFa induced inflammatory proximal tubular epithelia (iPT) responsible for Indian Hedgehog release in aged and fibrotic kidneys. Indian Hedgehog production by iPT cells activates canonical Hedgehog signalling in Gli1+ stromal cells leading to activation, proliferation and fibrosis deposition. Our data links the immune activation seen in aging and chronic kidney disease to cardio-renal fibrosis. This provides multiple targets for antifibrotic therapies which we validate in murine models of aging and kidney disease.
2023-01-30 | GSE178109 | GEO
Project description:Chronic kidney disease (CKD) is a burden for Public Health and concerns millions of individuals worldwide. Independently of the cause, CKD is secondary to the replacement of functional renal tissue by extra-cellular matrix proteins (i.e fibrosis) that progressively impairs kidney function. The pathophysiological pathways that control the development of renal fibrosis are common to most of the nephropathies involving native kidneys or kidney grafts. Unfortunately, very few treatments are available to stop renal fibrosis and most of the therapeutic strategies are often barely able to slow down the progression of fibrogenesis in native kidneys. Therefore, it is mandatory to discover new therapeutic pathways to stop renal fibrosis. Our objective is to study new pathways involved in renal fibrosis. We thus decided to use the model of Unilateral Ureteral renal Obstruction in mice, a fast and reproducible experimental model of renal fibrosis. We studied renal fibrosis using experimental model of ureteral unilateral obstruction in mice, which was performed by complete ligation of the left ureter. The control lateral right kidney served as internal control.
2013-02-10 | E-GEOD-38117 | biostudies-arrayexpress
Project description:Chronic kidney disease (CKD) has become one of the greatest threats to public health, characterized by renal fibrosis. However, no treatment targeting renal fibrosis is available so far. Several natural diterpene compounds exhibit extraordinary inhibitory effects on TGF-β1-induced renal fibroblast activation and renal fibrosis in UUO mouse model. RNA-sequencing reveals the signaling pathways affected by these compounds. The direct target of the compounds are explored via quantitative mass spectrometry. Besides, the efficacies of the compounds are compared with pirfenidone, an FDA-approved drug for idiopathic pulmonary fibrosis, which is under clinical trials for treating CKD patients. Moreover, these compounds exhibit more potent anti-fibrotic activities than conventional CKD medications such as valsartan and enalapril. Taken together, our study discovered that these diterpeniods alleviate kidney fibrosis by blocking the pro-fibrotic signaling pathway, which has great potential for the treatment of CKD.
2023-10-20 | GSE243694 | GEO
Project description:Cellular senescence is associated with the progression of chronic kidney disease (CKD), and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. We established three animal models related to Chronic Kidney Disease, including aristolochic acid nephropathy (AAN), bilateral ischemia/reperfusion injury (BIRI) and unilateral ureter obstruction (UUO). By RNA sequencing analysis in AAN, BIRI and UUO mice, we observed significant changes of senescence and fibrosis related genes.
2024-02-03 | GSE254440 | GEO
Project description:Renal fibrosis is a common consequence of various progressive nephropathies, including obstructive nephropathy, and ultimately leads to kidney failure. Infiltration of inflammatory cells is a prominent feature of renal injury after draining blockages from the kidney, and correlates closely with the development of renal fibrosis. However, the underlying molecular mechanism behind the promotion of renal fibrosis by inflammatory cells remains unclear. Herein, we showed that unilateral ureteral obstruction (UUO) induced Gasdermin D (GSDMD) activation in neutrophils, abundant neutrophil extracellular traps (NETs) formation and macrophage-to-myofibroblast transition (MMT) characterized by α-smooth muscle actin (α-SMA) expression in macrophages. Gsdmd deletion significantly reduced infiltration of inflammatory cells in the kidneys and inhibited NETs formation, MMT and thereby renal fibrosis. Chimera studies confirmed that Gsdmd deletion in bone marrow-derived cells, instead of renal parenchymal cells, provided protection against renal fibrosis. Further, specific deletion of Gsdmd in neutrophils instead of macrophages protected the kidney from undergoing fibrosis after UUO. Single-cell RNA sequencing identified robust crosstalk between neutrophils and macrophages. In vitro, GSDMD-dependent NETs triggered p65 translocation to the nucleus, which boosted the production of inflammatory cytokines and α-SMA expression in macrophages by activating TGF-β1/Smad pathway. In addition, we demonstrated that caspase-11, that could cleave GSDMD, was required for NETs formation and renal fibrosis after UUO. Collectively, our findings demonstrate that caspase-11/GSDMD-dependent NETs promote renal fibrosis by facilitating inflammation and MMT, therefore highlighting the role and mechanisms of NETs in renal fibrosis.
2024-04-19 | GSE264184 | GEO
Project description:Chronic kidney disease (CKD) is a burden for Public Health and concerns millions of individuals worldwide. Independently of the cause, CKD is secondary to the replacement of functional renal tissue by extra-cellular matrix proteins (i.e fibrosis) that progressively impairs kidney function. The pathophysiological pathways that control the development of renal fibrosis are common to most of the nephropathies involving native kidneys or kidney grafts. Unfortunately, very few treatments are available to stop renal fibrosis and most of the therapeutic strategies are often barely able to slow down the progression of fibrogenesis in native kidneys. Therefore, it is mandatory to discover new therapeutic pathways to stop renal fibrosis. Our objective is to study new pathways involved in renal fibrosis. We thus decided to use the model of Unilateral Ureteral renal Obstruction in mice, a fast and reproducible experimental model of renal fibrosis.
2013-02-10 | GSE38117 | GEO
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. Total RNA obtained from FACS sorted mouse FoxD1-derivative interstitial cells from healthy or fibrotic kidneys
2016-02-16 | E-GEOD-76549 | biostudies-arrayexpress