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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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE230005 | GEO | 2023/06/25

REPOSITORIES: GEO

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Uromodulin-retention in thick ascending limb affects SCD1 in neighboring S3 proximal tubule in males: transcriptome studies in mouse models of Uromodulin-associated kidney disease

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

Transcriptional profiling of renal cells expressing wild type or mutant uromodulin isoforms.

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.

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Uromodulin-retention in thick ascending limb affects SCD1 in neighboring S3 proximal tubule in males: transcriptome studies in mouse models of Uromodulin-associated kidney disease

2014-10-01 | GSE58513 | GEO

Mechanistic interactions of uromodulin with the thick ascending limb: perspectives in physiology and hypertension.

Project description:Hypertension is a significant risk factor for cardiovascular disease and mortality worldwide. The kidney is a major regulator of blood pressure and electrolyte homeostasis, with monogenic disorders indicating a link between abnormal ion transport and salt-sensitive hypertension. However, the association between salt and hypertension remains controversial. Thus, there is continued interest in deciphering the molecular mechanisms behind these processes. Uromodulin (UMOD) is the most abundant protein in the normal urine and is primarily synthesized by the thick ascending limb epithelial cells of the kidney. Genome-wide association studies have linked common UMOD variants with kidney function, susceptibility to chronic kidney disease and hypertension independent of renal excretory function. This review will discuss and provide predictions on the role of the UMOD protein in renal ion transport and hypertension based on current observational, biochemical, genetic, pharmacological and clinical evidence.

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Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease

Project description:Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by UMOD mutations is characterized by strong interfamilial variability. We generated two mutant Umod knock-in mouse models, harbouring two mutations associated with drastic differences in kidney survival in ADTKD patients. We performed bulk RNA-sequencing of kidney extracts from Umod KI mice at an early (1 month) and advanced (4 months) stage of disease.

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Hepsin-mediated Processing of Uromodulin is Crucial for Salt-sensitivity and Thick Ascending Limb Homeostasis.

Project description:Uromodulin is a zona pellucida-type protein essentially produced in the thick ascending limb (TAL) of the mammalian kidney. It is the most abundant protein in normal urine. Defective uromodulin processing is associated with various kidney disorders. The luminal release and subsequent polymerization of uromodulin depend on its cleavage mediated by the serine protease hepsin. The biological relevance of a proper cleavage of uromodulin remains unknown. Here we combined in vivo testing on hepsin-deficient mice, ex vivo analyses on isolated tubules and in vitro studies on TAL cells to demonstrate that hepsin influence on uromodulin processing is an important modulator of salt transport via the sodium cotransporter NKCC2 in the TAL. At baseline, hepsin-deficient mice accumulate uromodulin, along with hyperactivated NKCC2, resulting in a positive sodium balance and a better adaptation to water deprivation. In conditions of high salt intake, defective uromodulin processing predisposes hepsin-deficient mice to a salt-wasting phenotype, with a decreased salt sensitivity. These modifications are associated with intracellular accumulation of uromodulin, endoplasmic reticulum-stress and signs of tubular damage. These studies expand the physiological role of hepsin and uromodulin and highlight the importance of hepsin-mediated processing of uromodulin for kidney tubule homeostasis and salt sensitivity.

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Uromodulin Regulates Murine Aquaporin-2 Activity via Thick Ascending Limb-Collecting Duct Cross-Talk during Water Deprivation.

Project description:Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin-2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross-talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment.

| S-EPMC9408883 | biostudies-literature

Transcriptional profiling of a mouse model of Uromodulin Associated Kidney Disease (UAKD)

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

Uromodulin retention in thick ascending limb of Henle's loop affects SCD1 in neighboring proximal tubule: renal transcriptome studies in mouse models of uromodulin-associated kidney disease.

Project description:Uromodulin-associated kidney disease (UAKD) is a hereditary progressive renal disease which can lead to renal failure and requires renal replacement therapy. UAKD belongs to the endoplasmic reticulum storage diseases due to maturation defect of mutant uromodulin and its retention in the enlarged endoplasmic reticulum in the cells of the thick ascending limb of Henle's loop (TALH). Dysfunction of TALH represents the key pathogenic mechanism of UAKD causing the clinical symptoms of this disease. However, the molecular alterations underlying UAKD are not well understood. In this study, transcriptome profiling of whole kidneys of two mouse models of UAKD, UmodA227T and UmodC93F, was performed. Genes differentially abundant in UAKD affected kidneys of both Umod mutant lines at different disease stages were identified and verified by RT-qPCR. Additionally, differential protein abundances of SCD1 and ANGPTL7 were validated by immunohistochemistry and Western blot analysis. ANGPTL7 expression was down-regulated in TALH cells of Umod mutant mice which is the site of the mutant uromodulin maturation defect. SCD1 was expressed selectively in the S3 segment of proximal tubule cells, and SCD1 abundance was increased in UAKD affected kidneys. This finding demonstrates that a cross talk between two functionally distinct tubular segments of the kidney, the TALH segment and the S3 segment of proximal tubule, exists.

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Sweet orange genes regulated by TAL effectors of Xanthomonas citri (Xc) or Xanthomonas aurantifolii pathotype C

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