The aging kidney is characterized by tubuloinflammaging, a phenotype associated with MHC-II gene expression
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ABSTRACT:
PROVIDER: PRJNA977652 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24765336_1.fastq.gz | Fastqsanger.gz | |||
| SRR24765336_2.fastq.gz | Fastqsanger.gz | |||
| SRR24765337_1.fastq.gz | Fastqsanger.gz | |||
| SRR24765337_2.fastq.gz | Fastqsanger.gz | |||
| SRR24765338_1.fastq.gz | Fastqsanger.gz |
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Project description:Introduction Even during physiologic aging, the kidney experiences a loss of mass and a progressive functional decline. This is clinically relevant as it leads to an increased risk of acute and chronic kidney disease. The kidney tubular system plays an important role in the underlying aging process, but the involved cellular mechanisms remain largely elusive. Methods Kidneys of 3-, 12- and 24-month-old male C57BL/6J mice were used for RNA sequencing, histological examination, immunostaining and RNA-in-situ-hybridization. Single cell RNA sequencing data of differentially aged murine and human kidneys was analyzed to identify age-dependent expression patterns in tubular epithelial cells. Senescent and non-senescent primary tubular epithelial cells from mouse kidney were used for in vitro experiments. Results During normal kidney aging, tubular cells adopt an inflammatory phenotype, characterized by the expression of MHC class II related genes. In our analysis of bulk and single cell transcriptional data we found that subsets of tubular cells show an age-related expression of Cd74, H2-Eb1 and H2-Ab1 in mice and CD74, HLA-DQB1 and HLADRB1 in humans. Expression of MHC class II related genes was associated with a phenotype of tubular cell senescence, and the selective elimination of senescent cells reversed the phenotype. Exposure to the Cd74 ligand MIF promoted a prosenescent phenotype in tubular cell cultures. Discussion Together, these data suggest that during normal renal aging tubular cells activate a program of ‘tubuloinflammaging’, which might contribute to age-related phenotypical changes and to increased disease susceptibility.
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Project description:We performed RNA-seq of non-irradiated and irradiated proximal tubular epithelial cells as well as RNA-seq of kidneys from different ages in order to analyze the gene expression profile of senescent tubular cells
2023-09-11 | GSE233718 | GEO
Project description:Major Histocompatibility Complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses. Neuronal MHC-I has been proposed to regulate developmental synapse elimination and tau pathology in Alzheimer’s disease (AD). Here we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia were the primary source of classical and non-classical MHC-I in mice and humans. Translating Ribosome Affinity Purification (TRAP)-qPCR analysis of 3-6 and 18-22 month old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was also enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I binding Leukocyte Immunoglobulin-like (Lilrs) and Paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell-autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in AD mouse models and human AD data is evident across numerous mouse models, methods, and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.
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Project description:Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension and diabetes, frequent consequences of obesity. Despite extensive studies the mechanisms determining susceptibility to CKD remain elusive. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity induced by High-Fat Diet (HFD)-fed female mice sensitizes aging-associated mechanism in kidneys of newborn mice. Tissue from the kidney cortex and the kidney medulla was collected from offspring of control or HFD-fed mice.
2022-12-31 | E-MTAB-10954 | biostudies-arrayexpress
Project description:Hypoxia-induced intrauterine growth restriction increases the risk for chronic diseases in adults, affecting more than 140 million high altitude residents worldwide. Still, not much is known about the fetal mechanisms that prone these individuals to disease. Using bottom-up proteomics and the kidney as a readout, we delineated a dichotomous response to chronic hypoxic stress, comprising mechanisms that promote survival, but also induce premature senescence. Combined outcome is the manifestation of a predetermined aging phenotype already during fetal development. This aging phenotype is associated with a characteristic biomarker profile in tissue and blood serum samples, exploitable for targeting and monitoring disease.
2022-01-13 | PXD018999 | Pride
Project description:Aging is accompanied by a gradual loss of systemic metabolic homeostasis, which is maintained by multiple-organs, especially the kidney and kidney. However, a systematic study of the regulatory networks and regulatory transcription factors (TFs) of aging in the kidney and kidney remains lacking. Here, we performed an integrated analysis of multi-omics datasets in the kidney and kidney from young and aged mice, including RNA-seq, reduced representation bisulfite sequencing (RRBS) and ATAC-seq datasets, which indicated that enhanced inflammation and dysregulated metabolism were conserved signatures in aged kidney and kidney in both the transcriptome and epigenome. Transcription factor and regulatory network analysis indicated that activation of AP-1 and SPI1 was responsible for enhanced inflammation, and down-regulation of HNFs and PPARs contributed to dysregulated metabolism in aged kidney and kidney. Importantly, we found that the activation of AP-1 was cellular autonomous in aged hepatic and renal cells. However, enhanced SPI1 was caused by elevated infiltration of macrophages. Importantly, inhibition of AP-1 with small molecule combination attenuated inflammation phenotypes of aging in vivo and in vitro. Taken together, our analysis revealed common signatures and regulatory TFs of aging in the kidney and kidney, providing novel targets for the development of anti-aging interventions.
2021-10-01 | GSE181797 | GEO
Project description:The plasminogen activator inhibitor-2 (PAI-2; encoded by the SerpinB2 gene) has been described in the context of macrophage activation and in cellular senescence. As both mechanisms are important in kidney disease we tested a possible role of PAI-2 in renal injury and repair. Methods:Aging, ischemia/reperfusion injury and unilateral ureteral obstruction were performed on the mice. Bone marrow was transplantefrom SerpinB2-/- to wild-type littermates and vice versa. Primary tubular cells and macrophages from SerpinB2-/- and wildtype mice were used for functional studies and transcriptional profiling. Results: PAI-2 expression was up-regulated in cultured senescent tubular cells and in kidneys of aged mice. In the lack of PAI-2 in SerpinB2-/- mice was associated with enhanced renal fibrosis and an inflammatory phenotype during aging and in kidney injury models. While acute injury was associated with fewer monocytes/macrophages in SerpinB2-/- kidneys the subsequent resolution of inflammation seen in wildtype kidneys was lacking in knockout mice. Conclusion: PAI-2 regulates renal aging, tubular damage, and resolution of inflammation. PAI-2 is crucial for kidney repair in mice .
2019-10-22 | GSE139156 | GEO
Project description:The kidney governs many physiological factors of the body, and the glomerulus is its core filtration unit. Glomeruli comprise of less than 1.5% of the kidney’s volume and thus are underrepresented in many analyses of the kidney, and require particular isolation methods. Aging is a major risk factor for kidney disease, yet despite the importance of proper glomerular function, we have limited knowledge of the changes that glomerular cells undergo during aging. Here we interrogate the aged mouse kidney, glomerulus and glomerular cells using various approaches, including single cell RNA sequencing (scRNA-Seq), to identify age and senescence associated changes at the tissue and cellular level. We show that the aged kidney and glomerulus undergo structural changes, including increased fibrosis, glomerulonephritis and expression of injury and senescence-associated markers. Lastly, we utilized our method for high-throughput analysis of mouse glomeruli to characterize cell-specific and age-related changes in glomerular cells. This analysis revealed a senescence-associated phenotype in aged mesangial cells, and emphasized the potential importance of mesangial cells and macrophages in this niche. Our study provides insights into the molecular and cellular changes of the aging glomerulus that suggest therapeutic targets for age-related renal dysfunction.
2024-09-01 | GSE240374 | GEO
Project description:The kidney is a complex organ that governs many physiological parameters. It is roughly divided into three parts, the renal pelvis, medulla, and cortex. Covering the cortex is the renal capsule, a serosal tissue that provides protection and forms a barrier for the kidney. Serosal tissues of many organs have been recently shown to play a vital role in homeostasis and disease. Analyses of the cells that reside in these tissues have identified distinct cell types with unique phenotypes. Surprisingly, despite the importance of serosal tissues, little is known about cells of the renal capsule. Here, we characterized this niche and found that it is mainly comprised of fibroblasts and macrophages, but also includes many other diverse cell types. Characterizing renal capsule- associated macrophages, we found that they consist of a distinct subset (i.e., TLF+ macrophages) that is nearly absent in the kidney parenchyma. Injury, disease, and other changes within the kidney, affected the cell composition and phenotype of the renal capsule, indicating its dynamic and vibrant response to changes within the organ parenchyma. Lastly, we studied age-related changes in the renal capsule and found that aging affected the cell composition and pro- inflammatory phenotype of macrophages, increased CD8 T cells and other lymphocyte counts, and promoted a senescence-associated phenotype in fibroblasts. Taken together, our data illustrate the complexity and heterogeneity of the renal capsule and its underlying changes during aging and disease, improving our understanding of the kidney serosa that may be valuable for novel renal therapies.
2024-02-01 | GSE239538 | GEO
Project description:The kidney governs many physiological factors of the body, and the glomerulus is its core filtration unit. Glomeruli comprise of less than 1.5% of the kidney’s volume and thus are underrepresented in many analyses of the kidney, and require particular isolation methods. Aging is a major risk factor for kidney disease, yet despite the importance of proper glomerular function, we have limited knowledge of the changes that glomerular cells undergo during aging. Here we interrogate the aged mouse kidney, glomerulus and glomerular cells using various approaches, including single cell RNA sequencing (scRNA-Seq), to identify age and senescence associated changes at the tissue and cellular level. We show that the aged kidney and glomerulus undergo structural changes, including increased fibrosis, glomerulonephritis and expression of injury and senescence-associated markers. Lastly, we utilized our method for high-throughput analysis of mouse glomeruli to characterize cell-specific and age-related changes in glomerular cells. This analysis revealed a senescence-associated phenotype in aged mesangial cells, and emphasized the potential importance of mesangial cells and macrophages in this niche. Our study provides insights into the molecular and cellular changes of the aging glomerulus that suggest therapeutic targets for age-related renal dysfunction.
2024-09-01 | GSE240373 | GEO