Similar Datasets
Project description:Mutations in PKD1 cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). To further investigate the impact of Pkd1 knockout on renal tubular cells, a direct reprogramming approach was applied. After direct reprogramming of mouse embryonic fibroblasts to induced renal tubular epithelial cells (iRECs), Pkd1 knockout iREC clones were generated by Cre-mediated recombination of floxed Pkd1 alleles. The knockout clones were compared to their corresponding wild type clones by RNA Sequencing and transcriptome profiling.
2022-11-22 | GSE148840 | GEO
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder caused by loss-of-function mutations in PKD1 or PKD2. Increased glycolysis is a prominent feature of the disease, but how it impacts on other metabolic pathways is unknown. Here, we present an analysis of mouse Pkd1 mutant cells and kidneys to investigate the metabolic reprogramming of this pathology. We show that loss of Pkd1 leads to profound metabolic changes that affect glycolysis, mitochondrial metabolism, and fatty acid synthesis (FAS). We find that Pkd1-mutant cells preferentially use glutamine to fuel the TCA cycle and to sustain FAS. Interfering with either glutamine uptake or FAS retards cell growth and survival. We also find that glutamine is diverted to asparagine via asparagine synthetase (ASNS). Transcriptional profiling of PKD1-mutant human kidneys confirmed these alterations. We find that silencing of Asns is lethal in Pkd1-mutant cells when combined with glucose deprivation, suggesting therapeutic approaches for ADPKD.
2019-06-07 | MTBLS677 | MetaboLights
Project description:The Pkd1 gene was inactivated by tamoxifen at postnatal day 30 (P30) to generate a chronic-onset conditional Pkd1 gene knockout mouse model. Without any intervention, micro cysts could be detected adjacent to renal medulla-corticomedullary junction in Pkd1-/- mice until P180 and cystic phenotype is severe at P300. However, under dehydration situation, the cyst growth was more accelerated and progressive. The dehydration protocol resulted in Pkd1-/- mice varying degrees of sweating and weight loss. Mice that were not provided water during the day (water at night (D-WAN)) and mice that had access to water during the day (water all time (D-WAT)) showed significantly more weight loss compared with the control Pkd1-/- mice, although they drank more water at night. Interestingly, although D-WAN Pkd1-/- mice and D-WAT Pkd1-/- mice lost approximately body weights after one-day dehydration, while cyst enlargement and renal dysfunction was much more severe in the D-WAN Pkd1-/- mice after two-month intervention.
2021-04-27 | E-MTAB-10449 | biostudies-arrayexpress
Project description:To identify potential transcriptional targets of Smyd2, we performed ChIP-sequencing (ChIP-seq) analysis in renal epithelial cells with an anti-Smyd2 antibody. We identified 91 potential Smyd2 target genes in Pkd1 wild type MEK cells and 116 potential Smyd2 target genes in Pkd1 null MEK cells. There were 14 genes identified in both Pkd1 wild type and null MEK cells. Thus, the number of potential Smyd2 target genes in Pkd1 null MEK cells are 116 - 14 = 102 genes
2017-08-30 | GSE97708 | GEO
Project description:Role of PC1 on Evs release in mDCT15 cells
| PRJNA862961 | ENA
Project description:Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness, however, it is uncertain if these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP activation. In summary, PKD1 mutations in cirrhotic livers exert adaptive functionality without increasing transformation risk.
2024-05-15 | GSE264521 | GEO
Project description:Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness, however, it is uncertain if these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP activation. In summary, PKD1 mutations in cirrhotic livers exert adaptive functionality without increasing transformation risk.
2024-05-15 | GSE264520 | GEO
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the PKD1 or PKD2 genes leading to progressive cyst growth and often ESKD. We have previously demonstrated that with loss of Pkd1 the tubules can enlarge without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. Here we compared the transcriptomes from inducible tubule-specific knock out of Pkd1 (PkdTKO) and the uninduced littermate mice kidneys as controls. RNA sequencing revealed significant upregulation of 17 metalloproteinases. Of these, A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1), expressed primarily by the proximal tubule, is the most significantly upregulated following loss of Pkd1 expression. Upregulation of Adamts1 in PkdTKO kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubule basement membrane (TBM) and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/ATKO) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/ATKO mice demonstrated slower cystic enlargement, improved BUN and creatinine and better survival than did PkdTKO mice. In conclusion, preventing Adamts1 upregulation following loss of tubular Pkd1 expression effectively reduced macrophage accumulation and TBM remodeling, slowing cyst growth and preserving renal function.
2024-09-30 | GSE270531 | GEO
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and
PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), which are required for the regulation
of the renal tubular diameter. Loss of polycystin function results in cyst formation. Atypical forms
of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident
proteins through mechanisms that are not well understood. Here, we investigate the function of
DNAJB11, an ER co-chaperone associated with atypical ADPKD. We generated mouse models with
constitutive and conditional Dnajb11 inactivation and Dnajb11-deficient renal epithelial cells to
investigate the mechanism underlying autosomal dominant inheritance, the specific cell types
driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic
kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis,
mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly
originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11
inactivation strongly influences disease severity. Furthermore, we identify impaired PC1 cleavage
as a potential mechanism underlying DNAJB11-dependent cyst formation. Proteomic analysis of
Dnajb11- and Pkd1-deficient cells reveals common and distinct pathways and dysregulated
proteins, providing a foundation to better understand phenotypic differences between different
forms of ADPKD.
| MSV000095951 | MassIVE
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is caused by muta1ons in PKD1 and
PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), which are required for the regula1on
of the renal tubular diameter. Loss of polycystin func1on results in cyst forma1on. Atypical forms
of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident
proteins through mechanisms that are not well understood. Here, we investigate the func1on of
DNAJB11, an ER co-chaperone associated with atypical ADPKD. We generated mouse models with
constitutive and conditional Dnajb11 inactivation and Dnajb11-deficient renal epithelial cells to
investigate the mechanism underlying autosomal dominant inheritance, the specific cell types
driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic
kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis,
mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly
originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11
inactivation strongly influences disease severity. Furthermore, we identify impaired PC1 cleavage as a potential mechanism underlying DNAJB11-dependent cyst formation. Proteomic analysis of Dnajb11- and Pkd1-deficient cells reveals common and distinct pathways and dysregulated proteins, providing a foundation to better understand phenotypic differences between different forms of ADPKD.
| MSV000095950 | MassIVE