Kidney fibrosis: from mechanisms to therapeutic medicines

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 17, 2023

Abstract Chronic kidney disease (CKD) is estimated to affect 10–14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading scarring, a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. fibrosis identified tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, vascular rarefaction. Fibrotic niche, where organ initiates, complex interplay between injured parenchyma (like tubular cells) multiple non-parenchymal cell lineages (immune mesenchymal located spatially within scarring areas. Although the mechanisms are complicated due kinds cells involved, with help single-cell technology, many key questions have been explored, such as what kind renal tubules profibrotic, myofibroblasts originate, which immune how communicate each other. In addition, genetics epigenetics deeper that regulate fibrosis. And reversible nature epigenetic changes including DNA methylation, RNA interference, chromatin remodeling, gives an opportunity stop or reverse therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) developed delay progression recent years. Furthermore, better understanding also favored discover biomarkers fibrotic injury. review, we update advances mechanism summarize novel treatment for CKD.

Language: Английский

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Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function

Science, Journal Year: 2022, Volume and Issue: 376(6594)

Published: May 12, 2022

Understanding gene function and regulation in homeostasis disease requires knowledge of the cellular tissue contexts which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen types from 16 donors 25 samples, generating a cross-tissue atlas 209,126 nuclei profiles, integrated across tissues, donors, laboratory with conditional variational autoencoder. Using resulting atlas, highlight shared tissue-specific features tissue-resident cell populations; identify that might contribute neuromuscular, metabolic, immune components monogenic diseases biological processes involved their pathology; determine modules underlie mechanisms for complex traits analyzed by genome-wide association studies.

Language: Английский

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Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 6, 2022

Abstract The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic disease leads to injury changes in chromatin accessibility that modify the activity transcription factors involved metabolism inflammation. Here we use single nucleus RNA ATAC sequencing show diabetic reduced glucocorticoid receptor binding sites an injury-associated expression signature tubule. We hypothesize regulated by genetic background closely-intertwined with metabolic memory, which pre-programs respond differently external stimuli. Glucocorticoid excess has long been known increase risk for type 2 diabetes, raises possibility inhibition may mitigate adverse effects disease.

Language: Английский

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CellChat for systematic analysis of cell–cell communication from single-cell transcriptomics

Nature Protocols, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 16, 2024

Language: Английский

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Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP)

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(8), P. 1089 - 1100

Published: July 19, 2023

Language: Английский

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CellChat for systematic analysis of cell-cell communication from single-cell and spatially resolved transcriptomics

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 5, 2023

Abstract Recent advances in single-cell sequencing technologies offer an opportunity to explore cell-cell communication tissues systematically and with reduced bias. A key challenge is the integration between known molecular interactions measurements into a framework identify analyze complex networks. Previously, we developed computational tool, named CellChat that infers analyzes networks from RNA-sequencing (scRNA-seq) data within easily interpretable framework. quantifies signaling probability two cell groups using simplified mass action-based model, which incorporates core interaction ligands receptors multi-subunit structure along modulation by cofactors. v2 updated version includes direct incorporation of spatial locations cells, if available, infer spatially proximal communication, additional comparison functionalities, expanded database ligand-receptor pairs rich annotations, Interactive Explorer. Here provide step-by-step protocol for can be used both scRNA-seq resolved transcriptomic data, including inference analysis one dataset identification altered across different datasets. The steps applying transcriptomics are described detail. R implementation toolkit tutorials graphic outputs available at https://github.com/jinworks/CellChat . This typically takes around 20 minutes, no specialized prior bioinformatics training required complete task.

Language: Английский

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Decoding the tumor microenvironment with spatial technologies

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(12), P. 1982 - 1993

Published: Nov. 27, 2023

Language: Английский

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SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(5)

Published: Jan. 13, 2023

The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, healthy controls (HCs). Participants T2D obese had higher estimated glomerular filtration rates mesangial volumes than HCs. Ten participants been prescribed SGLT2i (T2Di[+]) 6 not (T2Di[-]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster highest T2Di(-) patients. However, transcriptional alterations treatment seen across nephron segments, particularly distal nephron. was associated suppression transcripts glycolysis, gluconeogenesis, tricarboxylic acid cycle pathways PT, but opposite effect thick ascending limb. Transcripts energy-sensitive mTORC1-signaling pathway returned toward HC levels all segments T2Di(+), consistent a mouse model treated SGLT2i. Decreased phosphorylated S6 protein tubules T2Di(+) patients confirmed changes mTORC1 activity. We propose that benefits kidneys mitigating diabetes-induced metabolic perturbations via signaling tubules.

Language: Английский

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STOmicsDB: a comprehensive database for spatial transcriptomics data sharing, analysis and visualization

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D1053 - D1061

Published: Nov. 11, 2023

Abstract Recent technological developments in spatial transcriptomics allow researchers to measure gene expression of cells and their locations at the single-cell level, generating detailed biological insight into processes. A comprehensive database could facilitate sharing transcriptomic data streamline acquisition process for researchers. Here, we present Spatial TranscriptOmics DataBase (STOmicsDB), a that serves as one-stop hub transcriptomics. STOmicsDB integrates 218 manually curated datasets representing 17 species. We annotated cell types, identified regions genes, performed cell-cell interaction analysis these datasets. features user-friendly interface rapid visualization millions cells. To further reusability interoperability data, developed standards archiving constructed system. Additionally, offer distinctive capability customizing dedicated sub-databases researchers, assisting them visualizing analyses. believe contribute research insights field, including archiving, sharing, analysis. is freely accessible https://db.cngb.org/stomics/.

Language: Английский

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SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

Science, Journal Year: 2024, Volume and Issue: 383(6685)

Published: Feb. 22, 2024

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach head-to-head comparison of injury-induced lineages, we identified dynamic switch in repairing epithelia. Lineages that regenerated epithelia silenced and healed (SOX9

Language: Английский

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