RNA-seq analysis of thick ascending limb (TAL) epithelium isolated from uromodulin (UMOD) deletion mutation mice and wild type (WT) mice at 16wks of age
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PROVIDER: PRJNA956952 | ENA |
REPOSITORIES: ENA
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Project description:Uromodulin is the most abundant urinary protein. It is exclusively produced and released in the urine by renal epithelial cells lining the thick ascending limb of Henle’s loop (TAL). Mutations in UMOD, the gene encoding uromodulin, cause autosomal dominant tubulointerstitial kidney disease uromodulin-related (ADTKD-UMOD). While the primary effect of all mutations, retention in the endoplasmic reticulum (ER), is well established, its downstream effects are still unknown. The aim of this study was to gain insight into ADTKD-UMOD pathogenesis through transcriptional profiling of immortalised mouse TAL cells (mTAL) transduced with lentiviral vectors encoding wild type or mutant (C150S) GFP-tagged human uromodulin.
2017-05-04 | GSE92704 | GEO
Project description:To gain insight into the mechanisms underlying the defective autophagic activity and its functional impact on the pathogenesis of disease, we performed RNA sequencing (RNA-seq) of mRNA isolated from TAL cells purified from heterozyous Umod deletion mutation mice (DEL/+) and Umod +/+ littermates at 16 weeks, the full-blown stage of the disease. Our analysis revealed that 9566 genes were significantly differentially expressed between mutant and WT TAL cells, including 4706 upregulated and 4860 downregulated.
2023-06-25 | GSE230005 | GEO
Project description:Freshly isolated rat kidney medullary thick ascending limbs were subjected for transcript profiling. Three microarray experiments were done to obtain the kidney medullary thick ascending limb transcriptome.
2009-01-26 | E-GEOD-13669 | biostudies-arrayexpress
Project description:Freshly isolated rat kidney medullary thick ascending limbs were subjected for transcript profiling.
2009-01-26 | GSE13669 | GEO
Project description:Uromodulin-associated kidney disease (UAKD) summarizes different clinical features of an autosomal dominant heritable disease syndrome in humans with a proven uromodulin (UMOD) mutation involved. It is often characterized by hyperuricemia, gout, alteration of urine concentrating ability, as well as a variable rate of disease progression inconstantly leading to renal failure and histological alterations of the kidneys. We recently established the two Umod mutant mouse lines UmodC93F and UmodA227T on the C3H inbred genetic background both showing kidney defects analogous to those found in human UAKD patients. The aim of this study was the further analysis of the phenotypic alterations by examining the kidneys as primarily affected organs. Transcriptome and quantitative PCR analyses as well as IHC analyses found significant changes related to the phenotyping changes. 4 male mice of each mutant cohort (Umod C93F & Umod A227T) and the corresponding wildtype controls, each mutant mouse was compared to the mean of the corresponding wildtype including a technical replicate (dye swap)
2014-10-01 | E-GEOD-58513 | biostudies-arrayexpress
Project description:Uromodulin (UMOD) is a secreted glycoprotein exclusively expressed by the cells lining the thick ascending limb of the loop of henle and the early distal tubule of the kidney nephron. Mutations in UMOD that interfere with proper folding of the protein are responsible for a progressive form of interstitial fibrotic kidney disease that leads to end stage renal disease, referred to as Uromodulin Associated Kidney Disease (UAKD). To assess key transcriptional changes associated with the progression of UAKD, we generated a knock-in mouse model harboring the mouse equivalent of the human mutation C148W. We profiled both the whole kidney tissue, as well as the specific UMOD+ cell populaitons in mutant and wild type mice. Analysis of differentially expressed genes in whole tissue and UMOD+ cells revealed a strong TNF-signaling signature, as well as TRIB3 upregulation, which is a key mediator of the intrinsic ER-stress mediated cell death pathway.
2017-09-01 | GSE102566 | GEO
Project description:Uromodulin (Tamm-Horsfall protein, THP) is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs (TAL) apically in the urine, and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supra-molecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the C terminus. However, THP in the circulation is not polymerized, and it remains unclear if non-aggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a non-polymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP+EHP) and established its presence in the urine in a non-polymerized native state. Proteomic characterization of urinary THP+EHP revealed its C-terminus to end at F617. In the human kidney, THP+EHP was not only detected in TAL cells, but also diffusely in the renal parenchyma. Using C-terminus proteomic sequencing and immunoblotting, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury (AKI), admission urinary THP+EHP was significantly lower in patients who subsequently developed AKI during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of non-polymerizing THP in the circulation. Larger studies as needed to establish the utility of urinary THP+EHP as a sensitive biomarker of kidney health and susceptibility to injury.
2022-11-08 | PXD027914 | Pride
Project description:Uromodulin-associated kidney disease (UAKD) summarizes different clinical features of an autosomal dominant heritable disease syndrome in humans with a proven uromodulin (UMOD) mutation involved. It is often characterized by hyperuricemia, gout, alteration of urine concentrating ability, as well as a variable rate of disease progression inconstantly leading to renal failure and histological alterations of the kidneys. We recently established the two Umod mutant mouse lines UmodC93F and UmodA227T on the C3H inbred genetic background both showing kidney defects analogous to those found in human UAKD patients. The aim of this study was the further analysis of the phenotypic alterations by examining the kidneys as primarily affected organs. Transcriptome and quantitative PCR analyses as well as IHC analyses found significant changes related to the phenotyping changes.
2014-10-01 | GSE58513 | GEO
Project description:Background: Uromodulin (Tamm-Horsfall) protein is secreted by the thick ascending limb into urine and crosses the basolateral membrane into the kidney interstitium and blood. Uromodulin may engage the kidney’s innate immune system with pro and anti-inflammatory effects described. Mutations in the UMOD gene are a cause of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to protein misfolding and endoplasmic reticulum stress. We identified a family with a UMOD mutation (C106F) that leads to glomerular and interstitial inflammation atypical for ADTKD. Methods: To determine if the observed phenotype is due to mutant uromodulin induced changes in the innate or adaptive immune system, we developed a transgenic (tg) mouse with a homologous cysteine to phenylalanine mutation (C105F) in the UMOD gene using CRISPR-Cas9 gene editing. Results: LLC-PK1 cells expressing wt and mutant protein had increased basolateral secretion of protein compared with cells expressing wt or mutant protein alone. EM examination of mutant medium showed protein aggregates in contrast to filaments in wt medium. Immunoprecipitation of plasma uromodulin from mutant mice demonstrated aggregate formation not seen in wt mice. Tg/+ mice displayed increased F4/80+ mononuclear phagocyte (MP) and podocyte inflammasome activity at baseline. Tg/+ mice developed glomerular and interstitial matrix deposition, myofibroblast proliferation and increased Creatinine with aging. Following ischemia-reperfusion injury, tg/+ mice had no increase in inflammasome activation over baseline in contrast to wt littermates and displayed improved tubular repair and renal function at 7 days. Differential gene expression analysis by RNA sequencing of kidney MP revealed activation of the ATF4 mediated stress response pathway and genes associated with the development of tissue fibrosis. Conclusions: The C106F mutation results in glomerular and interstitial inflammatory kidney disease due to interaction of aggregated misfolded protein with mononuclear phagocytic cells resulting in ER stress response. The resulting alteration in the immune system leads to improved kidney repair following acute injury but fibrosis and chronic renal failure with aging.
2020-08-23 | GSE139585 | GEO
Project description:Introduction: The effects of Uromodulin on the innate immune system remain uncertain. Mice with a cysteine to phenylalanine mutation (C105F) in the UMOD gene homologous to a pathogenic human mutation demonstrate high levels of circulating uromodulin following ischemia reperfusion kidney injury, increased markers of immune tolerance and improved kidney repair. We hypothesized that this may occur through interaction of circulating uromodulin with dendritic cells. Materials and Methods: Dendritic cells were isolated from WT and C105F mutant mice and used to compare gene expression using RNA sequencing. In vitro motility and efferocytosis assays were used to verify phenotypic changes predicted from affected pathways. Results: RNA sequencing demonstrated increased expression of scavenger receptor and motility associated genes. In vitro assays demonstrated that mutant uromodulin increased activation of the NF-kB pathway compared with WT protein and that mutant dendritic cells had increased migration and efferocytosis compared with WT cells. Discussion/Conclusion: Dendritic cells from mutant C105F mice display gene expression and phenotypic changes associated with increased scavenger receptor expression, motility and efferocytosis. These results suggest a possible mechanism of DC regulation by circulating uromodulin that may affect tissue repair following injury.
2022-08-06 | GSE210500 | GEO