Single-cell sequencing dissects the transcriptional identity of activated fibroblasts and identifies novel persistent distal tubular injury patterns in kidney fibrosis

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 3, 2024

Abstract Examining kidney fibrosis is crucial for mechanistic understanding and developing targeted strategies against chronic disease (CKD). Persistent fibroblast activation tubular epithelial cell (TEC) injury are key CKD contributors. However, cellular transcriptional landscapes of specific activated clusters remain elusive. Here, we analyzed single transcriptomic profiles two clinically relevant models which induced robust parenchymal remodeling. We dissected the molecular stroma newly identified three distinctive with “secretory”, “contractile” “vascular” enrichments. Also, both injuries generated failed repair TECs (frTECs) characterized by decline mature markers elevation stromal markers. Notably, frTECs shared identity distal nephron segments embryonic kidney. Moreover, that exhibited previously unrecognized spatial pattern TEC injury, outlined persistent renal including Krt8 Vcam1, while surviving proximal tubules (PTs) showed restored signature. also found long-term a prominent nephrogenic signature, Sox4 Hox gene elevation, prevailed in segments. Our findings might advance intervention fibrotic disease.

Язык: Английский

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PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(5)

Опубликована: Фев. 29, 2024

Ca2+-activated BK channels in renal intercalated cells (ICs) mediate luminal flow-induced K+ secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca2+-permeable channel expressed the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), cation-selective inhibitor GsMTx4 dampened increases intracellular Ca2+ concentration ([Ca2+]i), whereas PIEZO1 activator Yoda1 [Ca2+]i and activity. CCDs from mice fed high-K+ (HK) diet exhibited greater Yoda1-dependent increase than control diet. with targeted gene deletion Piezo1 (IC-Piezo1-KO) blunted response to or flow, an associated loss FIKS CCDs. Male IC-Piezo1-KO selectively blood [K+] oral bolus urinary excretion following volume challenge. Whole-cell expression BKα subunit was reduced HK conclude that mediates entry into upregulated CCD diet, necessary

Язык: Английский

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Spatiotemporal Landscape of Kidney Tubular Responses to Glomerular Proteinuria

Journal of the American Society of Nephrology, Год журнала: 2024, Номер unknown

Опубликована: Апрель 23, 2024

Key Points Glomerular proteinuria induces large-scale changes in gene expression along the nephron. Increased protein uptake proximal tubule results axial remodeling and injury. delivery to distal causes dedifferentiation of epithelium. Background Large increases glomerular filtration induce major body homeostasis are associated with a higher risk kidney functional decline cardiovascular disease. We investigated how elevated exposure modifies landscape tubular function entire nephron, understand cellular that mediate these important clinical phenomena. Methods conducted single-nucleus RNA sequencing, intravital imaging, antibody staining spatially map transport processes mouse tubule. then delineated were altered transgenic model inducible (POD-ATTAC) at 7 28 days. Results activated pleiotropic all nephron sections. Extension from early (S1) later (S2) parts initially triggered dramatic expansion hybrid S1/2 population, followed by injury failed repair, cumulative effect loss canonical S2 functions. Proteinuria also induced acute S3. Meanwhile, overflow luminal proteins caused transcriptional convergence between specialized regions generalized dedifferentiation. Conclusions modulated cell signaling epithelia distinct patterns segment-specific manner.

Язык: Английский

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Ion permeability profiles of renal paracellular channel‐forming claudins

Acta Physiologica, Год журнала: 2025, Номер 241(2)

Опубликована: Янв. 17, 2025

Members of the claudin protein family are major constituents tight junction strands and determine permeability properties paracellular pathway. In kidney, each nephron segment expresses a distinct subset claudins that form either barriers against solute transport or charge- size-selective channels. It was aim present study to compare permeation these renal ion channel-forming claudins. MDCK II cells, in which five had been knocked out (claudin quintupleKO), were stably transfected with individual mouse Cldn2, -4, -8, -10a, -10b, -15, dog Cldn16 -19, combination Cldn4 Cldn8, Cldn19. Permeation investigated Ussing chamber interactions by FRET assays. Claudin-4 -19 formed permeation. However, at low pH values absence HCO3 -, claudin-4 conveyed weak chloride nitrate permeability. Claudin-8 needed for assembly into TJ abolished this anion preference. Claudin-2, -16+19 highly permeable channels distinctive profiles different monovalent divalent anions cations, but ions opposite charge tracer fluorescein. Paracellular permeabilities along strictly determined expression patterns. specific certain thus lower transepithelial resistance, yet other solutes.

Язык: Английский

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Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

Pharmacological Reviews, Год журнала: 2022, Номер 74(3), С. 462 - 505

Опубликована: Июнь 16, 2022

The concept of local formation angiotensin II in the kidney has changed over last 10–15 years. Local synthesis angiotensinogen proximal tubule been proposed, combined with prorenin collecting duct. Binding via so-called (pro)renin receptor introduced, as well megalin-mediated uptake filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, metabolites other than [notably angiotensin-(1-7)] exist, and angiotensins exert their effects three different receptors, which type 2 Mas receptors are considered renoprotective, possibly a sex-specific manner, whereas 1 (AT₁) believed to be deleterious. Additionally, internalized may stimulate intracellular receptors. Angiotensin-converting enzyme (ACE2) not only generates angiotensin-(1-7) but also acts coronavirus receptor. Multiple, if all, cardiovascular diseases involve RAS, renal AT₁ often being claimed crucial role. Urinary RAS component levels, depending on filtration, reabsorption, release, reflect activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) novel (angiotensin receptor/neprilysin sodium-glucose cotransporter-2 soluble ACE2) affect formation, thereby displaying efficacy. Particular case latter three, an important question is what degree they induce renoprotection (e.g., RAS-dependent manner). This review provides unifying view, explaining how occurs it affected by why renoprotective when altering RAS.

Significance Statement

Angiotensin widely accepted little understood, multiple, contrasting concepts have put forward two decades. paper offers simultaneously interfering formation.

Язык: Английский

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ENaC activation by proteases

Acta Physiologica, Год журнала: 2022, Номер 235(1)

Опубликована: Март 11, 2022

Abstract Proteases are fundamental for a plethora of biological processes, including signalling and tissue remodelling, dysregulated proteolytic activity can result in pathogenesis. In this review, we focus on subclass membrane‐bound soluble proteases that defined as channel‐activating (CAPs), since they induce Na + ion transport through an autocrine mechanism when co‐expressed with the highly amiloride‐sensitive epithelial sodium channel (ENaC) Xenopus oocytes. These experiments first identified CAP1 (channel‐activating protease 1, prostasin) followed by CAP2 2, TMPRSS4) CAP3 3, matriptase) vitro mediators ENaC current. Since then, more serine‐, cysteine‐ metalloproteases were confirmed CAPs potentially cleave regulate ENaC, thus nomenclature was not further followed, but is accepted functional term or alias. The precise modulation has been fully elucidated. Studies organ‐specific knockout models revealed evidence their role increasing activity, although responsible activation yet to be identified. We summarize recent findings animal these respect implication activation. discuss consequences underlying phenotypes pathophysiological conditions, selected inhibitors. believe may present interesting therapeutic targets diseases aberrant homoeostasis.

Язык: Английский

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A comprehensive mouse kidney atlas enables rare cell population characterization and robust marker discovery

iScience, Год журнала: 2023, Номер 26(6), С. 106877 - 106877

Опубликована: Май 18, 2023

The kidney's cellular diversity is on par with its physiological intricacy; yet identifying cell populations and their markers remains challenging. Here, we created a comprehensive atlas of the healthy adult mouse kidney (MKA: Mouse Kidney Atlas) by integrating 140.000 cells nuclei from 59 publicly available single-cell single-nuclei RNA-sequencing datasets eight independent studies. To harmonize annotations across datasets, built hierarchical model populations. Our allows incorporation novel refinement known profiles as more become available. Using MKA learned hierarchies, predicted previously missing several allowed us to identify reproducible studies for poorly understood types transitional states, which verified using existing data micro-dissected samples spatial transcriptomics.

Язык: Английский

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The role of claudins in homeostasis

Nature Reviews Nephrology, Год журнала: 2023, Номер 19(9), С. 587 - 603

Опубликована: Июнь 21, 2023

Язык: Английский

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Multiomics Analyses Reveal Sex Differences in Mouse Renal Proximal Subsegments

Journal of the American Society of Nephrology, Год журнала: 2023, Номер 34(5), С. 829 - 845

Опубликована: Фев. 9, 2023

Significance Statement Sex-dependent differences in kidney function are recognized but the underlying molecular mechanisms largely unexplored. Advances genomics and proteomic technologies now allow extensive characterization of between same cell types males females. Multiomics integrating RNA-seq, ATAC-seq, proteomics data to investigate gene expression, chromatin accessibility, protein expression proximal tubules male female mice identified many sex-biased genes proteins associated with functions, including metabolic transport processes. Sex may also arise from variations interaction transcription factors accessible regions. A comprehensive web resource is provided advance understanding sex cells tubule. Background have been increasingly as important physiology pathophysiology, limited resources available for interrogation differences. Methods RNA-seq ATAC-seq microdissected mouse mass spectrometry homogenized perfused kidneys reveal tubule Results The transcriptomic indicated that major sexes were S2/S3 segments, most transcripts mapped autosomes rather than chromosomes. Many exhibiting involved monocarboxylic acid processes, organic anion transport, transport. method on captured accessibility. more 7000 differentially DNA regions distal Motif analyses revealed a lack direct involvement estrogen receptors or androgen receptor (absence canonical hormone response elements), suggesting an indirect regulatory role hormones. Instead, several (TFs) ( Tead1 , Nfia/b Pou3f3 ) whose interplay tubule-specific TFs e.g. Hnf1b Hnf4a contribute Finally, whole-kidney proteome was correlated transcriptome, Cyp2e1, Acsm2/3) identified. Conclusions cis-regulatory elements interact ways lead cells. These user-friendly page at https://esbl.nhlbi.nih.gov/MRECA/PT/.

Язык: Английский

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Advances in uromodulin biology and potential clinical applications

Nature Reviews Nephrology, Год журнала: 2024, Номер 20(12), С. 806 - 821

Опубликована: Авг. 19, 2024

Язык: Английский

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