Transcriptomic Profiling of Polycystic Kidney Disease Identifies Paracrine Factors in the Early Cyst Microenvironment
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ABSTRACT:
PROVIDER: PRJNA963178 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24351319_1.fastq.gz | Fastqsanger.gz | |||
| SRR24351319_2.fastq.gz | Fastqsanger.gz | |||
| SRR24351320_1.fastq.gz | Fastqsanger.gz | |||
| SRR24351320_2.fastq.gz | Fastqsanger.gz | |||
| SRR24351321_1.fastq.gz | Fastqsanger.gz |
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Project description:Adamts1 Promotes Cyst Expansion in Polycystic Kidney Disease
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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.
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Project description:To elucidate the molecular pathways that modulate renal cyst growth in autosomal dominant polycystic kidney disease (ADPKD) Keywords: Disease state analysis We performed global gene profiling on renal cysts of different size (small cysts: less than 1 ml, n=5; medium cysts: between 10-25 ml, n=5; large cysts: greater than 50 ml, n=3) and minimally cystic tissue (MCT, n=5) from five PKD1 polycystic kidneys. Additionally, non-cancerous renal cortical tissue from three nephrectomized kidneys with isolated renal cell carcinoma was used as normal control tissue (n=3). This dataset is part of the TransQST collection.
2009-08-14 | E-GEOD-7869 | biostudies-arrayexpress
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
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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
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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.
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Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
2021-07-15 | GSE179947 | GEO
Project description:Background: Autosomal dominant polycystic kidney disease (PKD) is characterized by extensive cyst formation and progressive fibrosis. However, the molecular mechanisms whereby the loss/loss-of-function of polycystin 1 or 2 (PC1/2) provokes fibrosis are largely unknown. The small GTPase RhoA has been implicated in cystogenesis, while we have shown that the RhoA/cytoskeleton/myocardin-related transcription factor (MRTF) pathway is a key inducer of epithelium-induced fibrogenesis. Therefore, we hypothesized that MRTF 1) is activated by PC1/2 loss, and 2) plays a critical role in fibrogenic repogramming of the epithelium and the subsequent induction of fibrosis. Methods: PC1/2 loss was achieved by gene silencing in tubular cells (in vitro) and in PKD1 (RC/RC) and PKD2 (ws25/-) mice (in vivo). RhoA activation was measured by pull-down assays and immunofluorescence. MRTF localization (nuclear/cytosolic ratio, intensity) was quantified in large cell populations and in renal tissue using automated image analysis. PC1/PC2 loss-promoted, MRTF-dependent gene expression was followed by qPCR, RNAseq and RNAscope. MRTF-dependent paracrine effects were assessed by a bioassay. Results: Loss of PC1 or PC2 activated RhoA in vitro and in vivo, resulting in cytoskeletal remodelling and robust nuclear MRTF translocation, accompanied by increased MRTF expression. Nuclear translocation occurred predominantly in dilated tubules, while overexpression in the cyst-lining epithelium. A large cohort of PC1/PC2 downregulation-induced genes was MRTF-dependent, including cytoskeletal, integrin-related, and matricellular/fibrogenic proteins. Epithelial MRTF was necessary for paracrine priming of fibroblast-myofibroblast transition. Conclusion: The Rho/MRTF pathway is a critical novel mediator of PC1/2 loss-induced acquisition of the profibrotic epithelial phenotype and the ensuing fibrosis.
2024-05-01 | GSE252716 | GEO
Project description:Melanin-like nanoparticles (MNPs) have recently emerged as valuable agents in antioxidant therapy due to their excellent biocompatibility and potent capacity to scavenge various reactive oxygen species (ROS). However, previous studies have mainly focused on acute ROS-related diseases, leaving a knowledge gap regarding their potential in chronic conditions. Furthermore, apart from their well-established antioxidant effects, it remains unclear whether MNPs target other intracellular molecular pathways. In this study, we synthesized ultra-small polyethylene glycol-incorporated Mn2+-chelated MNP (MMPP). We discovered that MMPP traversed the glomerular filtration barrier and specifically accumulated in renal tubules. Autosomal dominant polycystic kidney disease (ADPKD) is a chronic genetic disorder closely associated with increased oxidative stress and featured by the progressive enlargement of cysts originating from various segments of the renal tubules. Treatment with MMPP markedly attenuated oxidative stress levels, inhibited cyst growth, thereby improving renal function. Interestingly, we found that MMPP effectively inhibits a cyst-promoting gene program downstream of the cAMP-CREB pathway, a crucial signaling pathway implicated in ADPKD progression. Mechanistically, we observed that MMPP directly binds to the bZIP DNA-binding domain of CREB, leading to competitive inhibition of CREB's DNA binding ability and subsequent reduction in CREB target gene expression. Furthermore, by engineering an orally administrable formulation, we demonstrated that orally delivered-MMPP also effectively inhibits cyst growth. In summary, our findings highlight the potential of MMPP in delaying the progression of ADPKD by simultaneously targeting oxidative stress and CREB transcriptional activity.
2024-10-10 | GSE235269 | GEO