Tissue resident macrophages promote renal cystic disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE131896 | GEO | 2019/07/04
REPOSITORIES: GEO
Similar Datasets
Project description:Tissue resident macrophages promote renal cystic disease
| PRJNA545273 | ENA
Project description:BackgroundMutations affecting cilia proteins have an established role in renal cyst formation. In mice, the rate of cystogenesis is influenced by the age at which cilia dysfunction occurs and whether the kidney has been injured. Disruption of cilia function before postnatal day 12-14 results in rapid cyst formation; however, cyst formation is slower when cilia dysfunction is induced after postnatal day 14. Rapid cyst formation can also be induced in conditional adult cilia mutant mice by introducing renal injury. Previous studies indicate that macrophages are involved in cyst formation, however the specific role and type of macrophages responsible has not been clarified.MethodsWe analyzed resident macrophage number and subtypes during postnatal renal maturation and after renal injury in control and conditional Ift88 cilia mutant mice. We also used a pharmacological inhibitor of resident macrophage proliferation and accumulation to determine the importance of these cells during rapid cyst formation.ResultsOur data show that renal resident macrophages undergo a phenotypic switch from R2b (CD11clo) to R2a (CD11chi) during postnatal renal maturation. The timing of this switch correlates with the period in which cyst formation transitions from rapid to slow following induction of cilia dysfunction. Renal injury induces the reaccumulation of juvenile-like R2b resident macrophages in cilia mutant mice and restores rapid cystogenesis. Loss of primary cilia in injured conditional Ift88 mice results in enhanced epithelial production of membrane-bound CSF1, a cytokine that promotes resident macrophage proliferation. Inhibiting CSF1/CSF1-receptor signaling with a CSF1R kinase inhibitor reduces resident macrophage proliferation, R2b resident macrophage accumulation, and renal cyst formation in two mouse models of cystic disease.ConclusionsThese data uncover an important pathogenic role for resident macrophages during rapid cyst progression.
| S-EPMC6779366 | biostudies-literature
Project description:DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome.
2024-05-02 | GSE231487 | GEO
Project description:OBJECTIVE: Due to the common occurrence of peritumoral cysts throughout the central nervous system tumors, hemangioblastomas (HBs) provide a model of cyst to further study the molecular mechanisms of peritumoral cyst formation. METHODS: We conducted an integrated lipidomics and transcriptomics analysis on solid and cyst HB samples, to elucidate the changes in lipid profile and the expression levels of genes associated with lipid metabolism in the cyst formation. RESULTS: Transcriptomic analysis revealed differentially expressed genes between the solid and cystic HBs. The lipidomic analysis further showed a significant reduction in the abundance of triacylglycerol, ceramide, lysophosphatidylcholine, and lysophosphatidylethanolamine, and an increase in phosphatidylcholine and phosphatidylethanolamine in the cystic group. Besides, bioinformatics analysis revealed altered lipid biosynthesis, glycerophospholipid metabolism and phospholipase activity in the cyst HBs. CONCLUSION: Our findings indicate that aberrant lipid metabolism is a causative factor of cyst formation in HBs, and provide novel insights into the role of lipid metabolism in HBs.
2020-04-15 | GSE148216 | GEO
Project description:Chronic kidney disease is the main cause of mortality in patients with tuberous sclerosis complex disease (TSC). The mechanisms underlying TSC cystic kidney disease remain unclear with no available interventions to prevent cyst formation. Using targeted deletion of TSC1 in nephron progenitor cells, we showed that cysts in TSC1 null embryonic kidneys originate from injured proximal tubular cells with high mTOR complex 1 activity. Injection of rapamycin to pregnant mice inhibited the mTOR pathway and tubular cell proliferation in kidneys of TSC1 null offspring. Rapamycin also prevented renal cystogenesis and prolonged the life span of TSC newborns. Gene expression analysis of proximal tubule cells, identified sets of genes and pathways that were modified secondary to TSC1 deletion and rescued by rapamycin administration during nephrogenesis. Inflammation with mononuclear infiltration was observed in the cystic areas of TSC1 null kidneys. Dexamethasone administration during pregnancy decreased cyst formation not only by inhibiting the inflammatory response but also by interfering with the mTORC1 pathway. These results reveal novel mechanisms of cystogenesis in TSC disease and suggest new interventions prior to birth to ameliorate cystic disease in offspring.
2020-06-10 | GSE152165 | GEO
Project description:It is widely accepted that injuries to cilia mutant mice accelerate the rate of cystic kidney disease; however, cellular factors that drive the accelerated rate of cystic disease are unknown. By performing single cell RNA sequencing of all CD45+ immune cells, we find that the subtype and gene expression of adaptive immune cells is significantly altered between non-injured, aged cystic mice, injury-accelerated cystic mice, and non-cystic controls. Deletion of all adaptive immune cells reduced cystic disease in the injury-accelerated model but had no effect on cystic disease in the non-injured model. This differential rescue may be due to unique adaptive immune cell subtypes and ligands that are only present in the injury accelerated model of cystic disease.
2022-01-19 | GSE193528 | GEO
Project description:Fumarate hydratase (FH) mutations predispose to renal cysts cancer. These cancers overexpress hypoxia-inducible factor-alpha (Hif-1a). We have generated a conditional Fh1 (mouse FH) knockout mice that develop renal cysts and overexpress Hif-1a. In order to identify the contribution of Hif-1a to cyst formation we have intercrossed our mice with conditional HIf-1a KO mice. We intercrossed Fh1/Hif1a mice with kidney specific cre recombinase (Ksp-Cre) and analysed kidney cyst formation. RNA was extracted from cysts from 4xFh1 KO, 4xFh1/Hif-1a KO and 4 control mice. For each comparison littermates were used and the animals were aged 15 weeks i.e. early cystic disease.
2011-10-23 | E-GEOD-29988 | biostudies-arrayexpress
Project description:Nephronophthisis (NPHP) is a group of progressive renal disorders characterized by a variable number of cysts associated with cortical tubular atrophy. Recently, mutations in INV have been identified to be responsible for NPHP2. The inv/inv,inv-deltaC::GFP mouse that was created by introduction of inv gene lacking the C-terminus (inv-deltaC) into inv/inv mice develops multiple renal cysts without situs abnormality. Renal cyst progression was dependent on expression level of inv-deltaC transgene, suggesting that inv protein functions in a dose-dependent manner. Cell proliferation and apoptosis were increased in the inv-deltaC cystic kidneys. We searched up- and down-regulated genes during cyst development and progression using cDNA microarray. See appended table for comparison analysis of inv/inv,inv-deltaC::GFP vs +/+,inv-deltaC::GFP (GSM100334 vs GSM100335). Keywords: apoptosis, cell proliferation, gene expression, inv, inversin, polycystic kidney disease
2006-05-01 | GSE4462 | GEO
Project description:We applied unbiased cell type specific transcriptional profiling by translating ribosome affinity purification (TRAP) to mouse kidneys with polycystin-1 and cilia inactivation at a stage prior kidney tubule cyst formation. We identified differentially expressed actively translating mRNA that correlated with the cilia dependent cyst activation (CDCA) pattern common to male and female mice. This differential translatome offers opportunities for mechanistic discovery in polycystin and cilia related kidney phenotypes.
2024-02-23 | GSE232556 | GEO
Project description:Polycystic Kidney Disease (PKD) is a devastating inherited kidney disease that is a major cause of kidney failure. Large fluid-filled cysts develop in the kidney and continually expand over time, damaging the surrounding tissue until renal replacement therapy is required. Because the development of cysts is the major feature of this disease, researchers have long sought to determine the composition of cystic fluid. To the best of our knowledge, no one has previously published the ion concentrations of cystic fluid from any PKD rodent models. The overall goal of this study was to characterize the cyst fluid composition of a rat model of ARPKD, the PCK rat. This model developed spontaneously from the Charles River Japan cesarean derived Sprague Dawley (Crj:CD/SD) strain and features a mutation in Pkhd1, the ortholog to the causative ARPKD gene in humans. In addition to analyzing cystic fluid, we complemented our metabolomics approach with transcriptomic analysis of male and female PCK rat kidney cortex tissue.
2024-03-30 | GSE261500 | GEO