Impaired Endosome Maturation Mediates Tubular Proteinuria in Dent Disease Cell Culture and Mouse Models DOI Open Access
Katherine E. Shipman, Catherine J. Baty, Kimberly R. Long

et al.

Journal of the American Society of Nephrology, Journal Year: 2023, Volume and Issue: 34(4), P. 619 - 640

Published: Feb. 9, 2023

Significance Statement Loss of function the 2Cl − /H + antiporter ClC-5 in Dent disease causes an unknown impairment endocytic traffic, leading to tubular proteinuria. The authors integrated data from biochemical and quantitative imaging studies proximal tubule cells into a mathematical model determine that loss impairs endosome acidification delays early maturation cells, resulting reduced megalin recycling, surface expression, half-life. Studies mouse also revealed subsegment-specific differences effects knockout on subsegments. approach provides template dissect mutations or perturbations alter recovery filtered proteins level individual entire axis. Background uptake by kidney tubule, Reduced posttranslational stability cubilin, receptors bind recover proteins, is believed underlie defect. How leads receptor expression remains unknown. Methods We used adapt traffic control cells. mice were performed describe effect S1 segment along Results predicts have rates exit endosomes, decreased Early endosomes had lower [Cl ] higher pH. observed more profound expressing pathogenic E211G mutant. Alterations cellular distribution consistent with delayed recycling. Greater reductions S2 compared S1, consequences profile protein retrieval Conclusions Delayed due impaired accumulation primary mediator proteinuria disease. Rapid critical for efficient proteins.

Language: Английский

An atlas of healthy and injured cell states and niches in the human kidney DOI Creative Commons
Blue B. Lake, Rajasree Menon, Seth Winfree

et al.

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

Citations

358
Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications DOI Creative Commons
Bruce A. Molitoris, Ruben M. Sandoval, Shiv Pratap Singh Yadav

et al.

Physiological Reviews, Journal Year: 2022, Volume and Issue: 102(4), P. 1625 - 1667

Published: April 4, 2022

For nearly 50 years the proximal tubule (PT) has been known to reabsorb, process, and either catabolize or transcytose albumin from glomerular filtrate. Innovative techniques approaches have provided insights into these processes. Several genetic diseases, nonselective PT cell defects, chronic kidney disease (CKD), acute injury lead significant albuminuria, reaching nephrotic range. Albumin is also stimulate cascades. Thus, mechanisms of reabsorption, catabolism, transcytosis are being reexamined with use that allow for novel molecular cellular discoveries. Megalin, a scavenger receptor, cubilin, amnionless, Dab2 form multireceptor complex mediates binding uptake directs proteins lysosomal degradation after endocytosis. mediated by pH-dependent affinity neonatal Fc receptor (FcRn) in endosomal compartments. This reclamation pathway rescues urinary losses extending its serum half-life. altered oxidation, glycation, carbamylation because other bound ligands do not bind FcRn traffics lysosome. sorting mechanism reclaims physiological eliminates potentially toxic albumin. The clinical importance metabolism increased as now used therapeutic agents extend their half-life minimize filtration injury. purpose this review update integrate evolving information regarding reabsorption processing cells including discussion disorders considerations.

Language: Английский

Citations

86
Metabolic Communication by SGLT2 Inhibition DOI Creative Commons
A. Billing, Young Chul Kim, Søren Gullaksen

et al.

Circulation, Journal Year: 2023, Volume and Issue: 149(11), P. 860 - 884

Published: Dec. 28, 2023

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but underlying mechanism remains poorly understood. METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or secondary to improvement SGLT2i, we performed an in-depth proteomics, phosphoproteomics, metabolomics analysis integrating signatures from multiple metabolic organs body fluids after 1 week treatment nondiabetic as well diabetic mice with early uncomplicated hyperglycemia. RESULTS: Kidneys reacted most strongly in terms proteomic reconfiguration, including evidence for less proximal tubule glucotoxicity a broad downregulation apical uptake transport machinery (including sodium, glucose, urate, purine bases, amino acids), supported mouse human interactome studies. affected heart liver signaling, more reactive included white adipose tissue, showing lipolysis, and, particularly, gut microbiome, lower relative abundance bacteria taxa capable fermenting phenylalanine tryptophan cardiovascular uremic toxins, resulting plasma levels these compounds p-cresol sulfate). was detectable murine stool samples its addition microbiota fermentation recapitulated some microbiome findings, suggesting direct inhibition aromatic acids tryptophan. In lacking patients decompensated failure diabetes, likewise reduced circulating sulfate, impaired contractility rhythm induced pluripotent stem cell–derived engineered tissue. CONCLUSIONS: formation toxins such sulfate thereby their exposure need renal detoxification, which, combined kidney transporters acid, urate uptake), provides foundation protection.

Language: Английский

Citations

63
Targeted Single-Cell RNA-seq Identifies Minority Cell Types of Kidney Distal Nephron DOI Creative Commons
Lihe Chen,

Chun-Lin Chou,

Mark A. Knepper

et al.

Journal of the American Society of Nephrology, Journal Year: 2021, Volume and Issue: 32(4), P. 886 - 896

Published: March 4, 2021

Proximal tubule cells dominate the kidney parenchyma numerically, although less abundant cell types of distal nephron have disproportionate roles in water and electrolyte balance.Coupling a FACS-based enrichment protocol with single-cell RNA-seq profiled transcriptomes 9099 from thick ascending limb (CTAL)/distal convoluted (DCT) region mouse nephron.Unsupervised clustering revealed Slc12a3+/Pvalb+ Slc12a3+/Pvalb- cells, identified as DCT1 DCT2 respectively. appear to be heterogeneous, orthogonally variable expression Slc8a1, Calb1, Ckb. An additional subcluster showed marked cycle-/cell proliferation-associated mRNAs (e.g., Mki67, Stmn1, Top2a), which fit known plasticity DCT cells. No DCT2-specific transcripts were found. contrast by epithelial sodium channel β- γ-subunits much stronger associated calcium transport (Trpv5, S100g, Slc8a1). Additionally, scRNA-seq three distinct CTAL (Slc12a1+) subtypes. One these expressed Nos1 Avpr1a, consistent macula densa The other two clusters distinguished Cldn10 Ptger3 one Cldn16 Foxq1 other. These also alternative Iroquois homeobox transcription factors, Irx1 Irx2 Cldn10+ Irx3 Cldn16+ cells.Single-cell transcriptomics unexpected diversity among mouse. Web-based data resources are provided for data.

Language: Английский

Citations

91
An atlas of healthy and injured cell states and niches in the human kidney DOI Open Access
Blue B. Lake, Rajasree Menon, Seth Winfree

et al.

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

Citations

76
Human ureteric bud organoids recapitulate branching morphogenesis and differentiate into functional collecting duct cell types DOI
Min Shi, Kyle W. McCracken, Ankit Patel

et al.

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 41(2), P. 252 - 261

Published: Aug. 29, 2022

Language: Английский

Citations

49
Single-cell profiling of healthy human kidney reveals features of sex-based transcriptional programs and tissue-specific immunity DOI Creative Commons
Caitríona M. McEvoy, Julia Murphy, Lin Zhang

et al.

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

Published: Dec. 10, 2022

Abstract Knowledge of the transcriptional programs underpinning functions human kidney cell populations at homeostasis is limited. We present a single-cell perspective healthy from 19 living donors, with equal contribution males and females, profiling transcriptome 27677 cells to map high resolution. Sex-based differences in gene expression within proximal tubular were observed, specifically, increased anti-oxidant metallothionein genes females aerobic metabolism-related males. Functional metabolism confirmed cells, male exhibiting higher oxidative phosphorylation levels energy precursor metabolites. identified kidney-specific lymphocyte unique profiles indicative kidney-adapted functions. Significant heterogeneity myeloid was MRC1 + LYVE1 FOLR2 C1QC population representing predominant kidney. This study provides detailed cellular kidney, explores complexity parenchymal kidney-resident immune cells.

Language: Английский

Citations

48
A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury in patients with stone disease DOI Creative Commons
Victor Hugo Canela, William S. Bowen, Ricardo Melo Ferreira

et al.

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

Published: July 19, 2023

Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular molecular niche of human renal papilla in patients with calcium oxalate (CaOx) healthy subjects. addition to identifying cell types important papillary physiology, characterize collecting duct subtypes an undifferentiated epithelial type that was more prevalent patients. Despite focal nature mineral deposition nephrolithiasis, uncover a global injury signature characterized by immune activation, oxidative stress extracellular matrix remodeling. We also identify association MMP7 MMP9 expression deposition, respectively. are significantly increased urine CaOx disease, their levels correlate activity. Our results define spatial landscape specific pathways contributing stone-mediated associated urinary biomarkers.

Language: Английский

Citations

40
Sex differences in renal transporters: assessment and functional consequences DOI
Alicia A. McDonough, Autumn N. Harris, Lingyun Xiong

et al.

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 20(1), P. 21 - 36

Published: Sept. 8, 2023

Language: Английский

Citations

30
The role of the farnesoid X receptor in kidney health and disease: a potential therapeutic target in kidney diseases DOI Creative Commons
Dong-Hyun Kim, Jung Sun Park, Hoon‐In Choi

et al.

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(2), P. 304 - 312

Published: Feb. 3, 2023

Abstract The prevalence of kidney diseases has been increasing worldwide due to the aging population and results in an increased socioeconomic burden as well morbidity mortality. A deep understanding mechanisms underlying physiological regulation pathogenesis related can help identify potential therapeutic targets. farnesoid X receptor (FXR, NR1H4) is a primary nuclear bile acid that transcriptionally regulates homeostasis glucose lipid metabolism multiple tissues. roles FXR tissues other than hepatic intestinal are poorly understood. In studies over past decade, demonstrated have protective effect against through its anti-inflammatory antifibrotic effects; it also plays kidney. this review, we discuss role pathophysiological various diseases, including acute injury chronic diabetic nephropathy, fibrosis. Therefore, regulatory involving receptors, such FXR, physiology pathophysiology development agonists antagonists for modulating expression activation should be elucidated targets treatment diseases.

Language: Английский

Citations

27