An atlas of healthy and injured cell states and niches in the human kidney

Nature, Journal Year: 2023, Volume and Issue: 619(7970), P. 585 - 594

Published: July 19, 2023

Abstract Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles interactions within tissue neighbourhoods 1 . Here we applied multiple single-cell single-nucleus assays (>400,000 nuclei or cells) spatial imaging technologies to a broad spectrum healthy reference kidneys (45 donors) diseased (48 patients). This has provided high-resolution cellular atlas 51 main types, which include rare previously undescribed populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors localizations spanning entire kidney. We also define 28 states across nephron segments interstitium that were altered in injury, encompassing cycling, adaptive (successful maladaptive repair), transitioning degenerative states. Molecular signatures permitted localization these injury using transcriptomics, while large-scale 3D analysis (around 1.2 million neighbourhoods) corresponding linkages active immune responses. These analyses defined biological pathways are relevant time-course niches, including underlying epithelial repair predicted with decline function. integrated multimodal human represents comprehensive benchmark neighbourhoods, outcome-associated publicly available interactive visualizations.

Language: Английский

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Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(27)

Published: June 28, 2021

Significance A single acute kidney injury event increases the risk of progression to chronic disease (CKD). Combining single-nucleus RNA sequencing with genetic tracing injured proximal tubule cells identified a spatially dynamic, evolving response following ischemia–reperfusion injury. Failed repair leads persistence profibrotic, proinflammatory Vcam1 + / Ccl2 cell type exhibiting senescence-associated secretory phenotype and marked transcriptional activation NF-κB AP-1 pathway signatures, but no signs G 2 /M cycle arrest. Insights from this study can inform strategies improve renal prevent CKD progression.

Language: Английский

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Aging is associated with a systemic length-associated transcriptome imbalance

Nature Aging, Journal Year: 2022, Volume and Issue: 2(12), P. 1191 - 1206

Published: Dec. 9, 2022

Abstract Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, show that transcript length alone explains transcriptional changes observed with aging in mice humans. We present three lines evidence supporting biological importance uncovered transcriptome imbalance. First, vertebrates association primarily displays lower relative abundance long transcripts aging. Second, eight antiaging interventions Interventions Testing Program National Institute on can counter this association. Third, find humans genes longest enrich reported to extend lifespan, whereas those shortest shorten lifespan. Our study opens fundamental questions organization transcriptomes.

Language: Английский

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Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(9), P. 2450 - 2460

Published: Aug. 8, 2024

Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity mortality. Here we developed a proteomic age clock the UK Biobank (n = 45,441) using platform comprising 2,897 explored its utility predict major disease morbidity mortality diverse populations. We identified 204 that accurately chronological (Pearson r 0.94) found aging was associated with incidence of 18 chronic diseases (including heart, liver, kidney lung, diabetes, neurodegeneration cancer), as well all-cause risk. Proteomic also measures biological, physical cognitive function, including telomere length, frailty index reaction time. Proteins contributing most substantially are involved numerous functions, extracellular matrix interactions, immune response inflammation, hormone regulation reproduction, neuronal structure function development differentiation. In validation study involving biobanks China 3,977) Finland 1,990), showed similar accuracy 0.92 0.94, respectively) compared performance Biobank. Our results demonstrate involves spanning multiple functional categories status, across geographically genetically

Language: Английский

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Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney

eLife, Journal Year: 2021, Volume and Issue: 10

Published: March 9, 2021

Little is known about the molecular changes that take place in kidney during aging process. In order to better understand these changes, we measured mRNA and protein levels genetically diverse mice at different ages. We observed distinctive change as a function of age. Changes both are associated with increased immune infiltration decreases mitochondrial function. Proteins show greater extent reveal wide array biological processes including unique, organ-specific features kidney. Most importantly, functionally important age-related occur absence corresponding mRNA. Our findings suggest profiling alone provides an incomplete picture examination proteins essential not transcriptionally regulated.

Language: Английский

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An atlas of healthy and injured cell states and niches in the human kidney

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: July 29, 2021

Abstract Understanding kidney disease relies upon defining the complexity of cell types and states, their associated molecular profiles, interactions within tissue neighborhoods. We have applied multiple single-cell or -nucleus assays (>400,000 nuclei/cells) spatial imaging technologies to a broad spectrum healthy reference (n = 42) kidneys. This has provided high resolution cellular atlas 100 that include rare novel populations. The multi-omic approach provides detailed transcriptomic epigenomic regulatory factors, localizations for major spanning entire kidney. further identify define states altered in injury, encompassing cycling, adaptive maladaptive repair, transitioning degenerative affecting several segments. Molecular signatures these permitted localization injury neighborhoods using transcriptomics, large-scale 3D analysis ∼1.2 million linkages active immune responses. These analyses defined biological pathways relevant niches, including underlying transition from predicted were with decline function during chronic disease. human atlas, neighborhoods, will be valuable resource future studies.

Language: Английский

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Global and tissue-specific aging effects on murine proteomes

Cell Reports, Journal Year: 2023, Volume and Issue: 42(7), P. 112715 - 112715

Published: July 1, 2023

Maintenance of protein homeostasis degrades with age, contributing to aging-related decline and disease. Previous studies have primarily surveyed transcriptional aging changes. To define the effects age directly at level, we perform discovery-based proteomics in 10 tissues from 20 C57BL/6J mice, representing both sexes adult late midlife ages (8 18 months). Consistent previous studies, age-related changes abundance often no corresponding change. Aging results increases immune proteins across all tissues, consistent a global pattern infiltration age. Our protein-centric data reveal tissue-specific functional consequences, including altered endoplasmic reticulum trafficking spleen. We further observe stoichiometry complexes important roles homeostasis, CCT/TriC complex large ribosomal subunit. These provide foundation for understanding how contribute systemic tissues.

Language: Английский

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Micro and macroevolution of sea anemone venom phenotype

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 16, 2023

Abstract Venom is a complex trait with substantial inter- and intraspecific variability resulting from strong selective pressures acting on the expression of many toxic proteins. However, understanding processes underlying toxin dynamics that determine venom phenotype remains unresolved. By interspecific comparisons we reveal in sea anemones evolves rapidly each species different family dictates by massive gene duplication events. In-depth analysis anemone, Nematostella vectensis , revealed striking variation dominant ( Nv1 ) diploid copy number across populations (1-24 copies) independent expansion/contraction events, which generate distinct haplotypes. correlates at both transcript protein levels one population having near-complete loss production. Finally, establish hypothesis incorporates observations other venomous lineages animals have convergently evolved similar strategy shaping their venom.

Language: Английский

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Mitochondrial dysfunction and mitophagy blockade contribute to renal osteodystrophy in chronic kidney disease-mineral bone disorder

Kidney International, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(21), P. 2338 - 2358.e5

Published: Sept. 5, 2023

Language: Английский

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