American Journal Of Pathology, Journal Year: 2024, Volume and Issue: 195(1), P. 5 - 6
Published: Dec. 23, 2024
Language: Английский
Nature Reviews Nephrology, Journal Year: 2024, Volume and Issue: 20(10), P. 659 - 671
Published: May 8, 2024
Language: Английский
Citations
20
JCI Insight, Journal Year: 2025, Volume and Issue: 10(5)
Published: March 9, 2025
Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased CKD, and supplementation protective. However, both the mechanism how protects from as well cell types involved, poorly understood. Using mouse model Alport syndrome, we show nicotinamide riboside (NR), an precursor, stimulated PPARα signaling restored FAO proximal tubules, thereby protecting CKD sexes. Bulk RNA-sequencing showed pathways were mice activated by NR These transcriptional changes confirmed orthogonal imaging techniques biochemical assays. Single-nuclei RNA sequencing spatial transcriptomics, first their kind to our knowledge mice, tubule cells. Finally, also report, for time knowledge, sex differences at level this model. In summary, data herein identify nephroprotective they demonstrate benefit localizes
Language: Английский
Citations
0
American Journal of Kidney Diseases, Journal Year: 2023, Volume and Issue: 83(3), P. 402 - 410
Published: Oct. 13, 2023
Language: Английский
Citations
9
American Journal Of Pathology, Journal Year: 2024, Volume and Issue: unknown
Published: Aug. 1, 2024
Language: Английский
Citations
2
Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown
Published: Feb. 20, 2024
Abstract Maladaptive proximal tubular cells have been implicated in failure of repair following renal injury rodent models, however whether this translates to human kidney disease is unknown. Hence, we integrated snRNA-ATAC-seq with single-cell molecular imaging generate a multiomic atlas disease. In injured kidneys, subset epithelial acquired an inflammatory phenotype, enriched pro-fibrotic and senescence markers, analogous maladaptive mice. Cell neighborhood analysis positioned the phenotype adjacent leucocytes myofibroblasts ligand-receptor highlighted paracrine signaling from mediate leucocyte recruitment myofibroblast activation. Loss HNF4α-driven gene regulatory network activation NF-κβ AP-1 transcription factors epigenetically imprinted phenotype. Targeting these by administration inhibitor or senolytic agent ameliorated inflammation, expression senescence-associated transcripts fibrosis murine models suggesting as therapies for
Language: Английский
Citations
1
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: Feb. 29, 2024
ABSTRACT Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD + ) a small molecule that participates in hundreds of metabolism-related reactions. NAD levels are decreased CKD, and supplementation protective. However, both the mechanism how protects from as well cell types involved, poorly understood. Using mouse model Alport syndrome, we show nicotinamide riboside (NR), an precursor, stimulates peroxisome proliferator-activated receptor alpha signaling restores FAO proximal tubules, thereby protecting CKD sexes. Bulk RNA-sequencing shows pathways mice activated by NR These transcriptional changes confirmed orthogonal imaging techniques biochemical assays. Single nuclei spatial transcriptomics, first their kind mice, tubule cells. Finally, also report, for time, sex differences at level this model. In summary, identify nephroprotective demonstrate cells substantially contribute to benefit.
Language: Английский
Citations
1
Current Opinion in Nephrology & Hypertension, Journal Year: 2024, Volume and Issue: 33(4), P. 420 - 426
Published: April 8, 2024
Purpose of review Kidney fibrosis is a key pathological aspect and outcome chronic kidney disease (CKD). The advent multiomic analyses using human tissue, enabled by technological advances, marks new chapter discovery in research the kidney. This highlights rapid advancements single-cell spatial techniques that offer avenues for exploring questions related to development. Recent findings We recently focused on understanding origin transition myofibroblasts RNA sequencing (scRNA-seq) [1]. analysed cells from healthy kidneys compared them patient samples with CKD. identified PDGFRα+/PDGFRβ+ mesenchymal as primary cellular source extracellular matrix (ECM) fibrosis. found several commonly shared cell states fibroblasts provided insights into molecular regulators. Novel multiomics tools are now available shed light lineages, plasticity cell-cell communication Summary As further approaches being developed, opportunities apply these methods tissues expand similarly. Careful design optimisation experiments needed answer
Language: Английский
Citations
1
Bioscience Reports, Journal Year: 2024, Volume and Issue: 44(7)
Published: June 21, 2024
The intrarenal endothelin (ET) system is an established moderator of kidney physiology and mechanistic contributor to the pathophysiology progression chronic disease in humans rodents. aim present study was characterize ET by combining single cell RNA sequencing (scRNA-seq) data with immunolocalization human rodent kidneys both sexes. Using publicly available scRNA-seq data, we assessed sex status (human), age (rats), diurnal expression (mice) on expression. In normal biopsies sexes samples, endothelin-converting enzyme-1 (ECE1) ET-1 were prominent glomeruli endothelium. These agreed from these three species, ECE1/Ece1 mRNA enriched However, EDN1/Edn1 gene (encodes ET-1) rarely detected, even though it immunolocalized within kidneys, plasma urinary excretion are easily measured. Within each there some sex-specific differences. For example, living donors, men had a greater glomerular endothelial receptor B (Ednrb) compared women. mice, females Ednrb than male mice. As commercially antibodies did not work all always correlate protein levels, multiple approaches should be considered maintain required rigor reproducibility pre- clinical studies evaluating system.
Language: Английский
Citations
1
Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(8), P. 107520 - 107520
Published: June 29, 2024
Acute kidney injury (AKI) is a common condition associated with significant morbidity, mortality, and cost. Injured tissue can regenerate after many forms of AKI. However, there are no treatments in routine clinical practice to encourage recovery. In part, this shortcoming due an incomplete understanding the genetic mechanisms that orchestrate The advent high-throughput sequencing technologies mouse models has opened unprecedented window into transcriptional dynamics accompany both successful maladaptive repair. AKI recovery shares similar cell-state transformations development, which suggest gene regulation. Several powerful bioinformatic strategies have been developed infer activity regulatory networks by combining multiple data at single-cell resolution. These studies highlight not only shared stress responses but also key changes controlling metabolism. Furthermore, chromatin immunoprecipitation injured kidneys revealed dynamic epigenetic modifications enhancer elements near target genes. This review will how these enhanced our regulation response regeneration. affecting up 20% hospitalized patients contributes increased cost (1Silver S.A. Long J. Zheng Y. Chertow G.M. Cost acute patients.J. Hosp. Med. 2017; 12: 70-76Crossref PubMed Scopus (154) Google Scholar, 2Chertow Burdick E. Honour M. Bonventre J.V. Bates D.W. injury, Length Stay, costs Am. Soc. Nephrol. 2005; 16: 3365-3370Crossref (2770) Scholar). Remarkably, if degree sublethal. Unfortunately, stimulate or enhance regeneration other than supportive care practice, part owing molecular controls limit promote During repair, cell lineage tracing supports model where surviving tubular epithelial cells dedifferentiate, proliferate, eventually re-express specialized proximal tubule genes required for normal functions (reviewed Ref. (3Chang-Panesso Humphreys B.D. Cellular plasticity repair.Nat. Rev. 13: 39-46Crossref (106) Scholar)). To accomplish feat, must alter their stable patterns expression high cellular induced injury. Cells activate program survival repair while retaining memory original identity. Finally, they re-establish differentiated pattern indicative functional tubules. precise regulate re-entry mitosis remain poorly defined. recent advances methods, tractable models, integrated analyses Defining may identify novel kidney-specific targets suffering from transcription factors drive impact Kidney occur hemodynamic, toxic, obstructive insults. A cause severe transient ischemia leading death Refs. (4Basile D.P. Anderson M.D. Sutton T.A. Pathophysiology injury.Compr. Physiol. 2012; 2: 1303-1353Crossref (849) 5Venkatachalam M.A. Weinberg J.M. Kriz W. Bidani A.K. Failed recovery, AKI-CKD transition, disease progression.J. 2015; 26: 1765-1776Crossref (518) Of nephron segments, most sensitive type though segments occurs (6Lake B.B. Menon R. Winfree S. Hu Q. Ferreira R.M. Kalhor K. et al.An atlas healthy states niches human kidney.Nature. 2023; 619: 585-594Crossref (95) uses highly metabolism relies on oxidation fatty acids fuel energy-intensive resorption fluid electrolytes glomerular ultrafiltrate, predominantly performed segment. Concurrently, microvascular anatomy produces gradient oxygen availability cortex medulla (7Prasad P.V. Li L.-P. Hack B. Leloudas N. Sprague S.M. Quantitative Blood Oxygenation level dependent Magnetic Resonance Imaging estimating Intra-renal Demonstrates Hypoxemic CKD.Kidney Int. Rep. 8: 1057-1067Abstract Full Text PDF (0) Thus, setting hypoperfusion, mismatch between delivery demand results oxidative stress, via several pathways. processes S3 segment tubule, sits border (8Schaub J.A. Venkatachalam Proximal transition CKD.Kidney360. 2021; 355-364Crossref Scholar) (Fig. 1). damaged epithelium regenerate, restoring function some patients. we now appreciate rarely complete such who develop greater chance developing chronic progressing end-stage (9Venkatachalam Griffin K.A. Lan Geng H. Saikumar P. injury: springboard progression disease.Am. Ren. 2010; 298: F1078-F1094Crossref 10Schiffl Fischer Five-year outcomes requiring renal replacement therapy.Nephrol. Dial. Transplant. 2008; 23: 2235-2241Crossref 11Schiffl Renal necrosis therapy: prospective study critically ill patients.Nephrol. 2006; 21: 1248-1252Crossref (137) Over last 2 decades, more comprehensive emerged. Much work genetically modified Among widely used ischemia—reperfusion artery vein temporarily clamped then released. Alternatively, toxin include cisplatin, glycerol-induced rhabdomyolysis, aristolochic acid, folic lipopolysaccharides. rodent ischemia–reperfusion clamp closely resembles be focus review. While equivalent, organoids samples Precision Medicine Project 12Menon Bomback A.S. Lake Stutzke C. Grewenow Menez al.Integrated single histopathological reveal diverse participant clinical-molecular-pathologic correlation.Kidney 2022; 101: 1116-1125Abstract 13Gisch D.L. Brennan Basta Keller M.S. al.The landscape types kidney.Nat. Commun. 2024; 15: 433Crossref confirms homology among programs. engineered mice yield important insights humans manipulations possible. addressing origin repopulate led interpretations, including designated populations stem cells, bone marrow–derived mesenchymal resident epithelia. sophisticated mature survive initial dedifferentiate re-enter mitosis. Although disproportionately contribute (14Lazzeri Angelotti M.L. Peired A. Conte Marschner Maggi L. al.Endocycle-related hypertrophy progenitor proliferation recover injury.Nat. 2018; 9: 1344Crossref (175) Scholar), epithelia appear retain regenerative potential. neither evidence fixed pool nor nonkidney contributing (15Kusaba T. Lalli Kramann Kobayashi Differentiated tubule.Proc. Natl. Acad. Sci. U. 2014; 111: 1527-1532Crossref (363) 16Humphreys Valerius T.M. Mugford J.W. Soeung Duffield J.S. al.Intrinsic injury.Cell Stem Cell. 284-291Abstract (734) 17Berger Bangen J.-M. Hammerich Liedtke Floege Smeets al.Origin regenerating injury.Proc. 1533-1538Crossref (130) Rather, irreversibly tagged generate clones within regenerated tubules strongly support idea any proliferate tubule. Therefore, widespread robust activation markers (18Witzgall Brown D. Schwarz Localization proliferating nuclear antigen, vimentin, c-Fos, clusterin postischemic kidney. Evidence heterogenous large mitotically active dedifferentiated cells.J. Clin. Invest. 1994; 93: 2175-2188Crossref 19Humphreys Czerniak DiRocco Hasnain Cheema Repair does involve progenitors.Proc. 2011; 108: 9226-9231Crossref (302) likely represents intrinsic 15Kusaba 20Gerhardt L.M.S. Koppitch Gestel J.v. Guo Cho Wu al.Lineage single-Nucleus multiomics features adaptive injury.J. 34: 554-571Crossref (25) RNA-Seq datasets identified population reflect failed areas fibrosis ongoing inflammation (5Venkatachalam 21Kirita Uchimura Wilson P.C. Cell profiling reveals conserved 2020; 117: 15874-15883Crossref (274) 22Balzer Doke Yang Y.-W. Aldridge Mai al.Single-cell analysis highlights differences druggable pathways underlying fibrotic regeneration.Nat. 4018Crossref (72) 23Ide Ide Strausser Abe Herbek al.Ferroptotic promotes accumulation pro-inflammatory repair.Elife. 10e68603Crossref (69) 1D). Dedifferentiation, proliferation, developmental all similarities development (24Little Kairath Does Recapitulate development?.J. 2016; 28: 34-46Crossref (56) 25Chiba Hukriede de Caestecker M.P. regeneration: lessons development.Curr. Pathobiol. 3: 67-79Crossref (8) For discussion involved, see Schnell al., 2022 (26Schnell Achieng Lindström N.O. Principles development.Nat. 18: 628-642Crossref After gastrulation, develops region mesoderm called intermediate, as it located axial lateral plate 2). Two simple tubes nephric Wolffian ducts run bilaterally midthoracic posterior cloaca. At end, ureteric bud grows out duct invades metanephric mesenchyme initiate development. begins branch, ultimately forming much collecting system, whereas aggregates tips branching buds WNT signaling process mesenchyme-to-epithelial (MET) nephron. Also termed cap mesenchyme, express unique combinations Pax2, Six2, Cited1. primitive vesicle first comma-shaped subsequently s-shaped body patterned along proximal–distal axis Notch 2C). distal end connects form continuous end. Multiple conversion, elongation, cell–type specification. essential Pax2/8, WT1, Eya1, HNF1b, HNF4a, NOTCH intracellular domains. Prior induction bud, already predisposed toward fate expresses combination WT1 responding inductive signals whose deletion agenesis (27Kreidberg Sariola Loring Maeda Pelletier Housman al.WT-1 early development.Cell. 1993; 74: 679-691Abstract (1736) 28Torres Gomez-Pardo Dressler G.R. Gruss Pax-2 steps urogenital development.Development. 1995; 121: 4057-4065Crossref 29Brophy P.D. Ostrom Lang K.M. Regulation outgrowth Pax2-dependent glial derived neurotrophic factor gene.Development. 2001; 128: 4747-4756Crossref related protein Pax8 identical DNA-binding domain Pax2 expressed remains adult epithelia, downregulated system. Genetic redundancy Pax2/8 functions, (30Narlis Grote Gaitan Boualia S.K. Bouchard Morphogenesis differentiation kidney.J. 2007; 1121-1129Crossref (179) 31Laszczyk A.M. Higashi A.Y. Patel S.R. Johnson C.N. Soofi Abraham al.Pax2 proteins Urea Transporters Aquaporins control urine Concentration 31: 1212-1225Crossref (17) Recent Pax-dependent core driving MET cooperation HNF1b (32Ng-Blichfeldt J.-P. Stewart B.J. Clatworthy M.R. Williams Röper Identification mesenchymal-to-epithelial transition.Dev. 59: 595-612.e8Abstract induction, Six2 helps maintain undifferentiated state allows continued precocious exhaustion (33Self Lagutin O.V. Bowling Hendrix Cai al.Six2 suppression nephrogenesis renewal kidney.EMBO 25: 5214-5228Crossref (396) Inactivation progenitors rudimentary nephrons mostly fates, suggesting need correct patterning (34Heliot Desgrange Buisson I. Prunskaite-Hyyryläinen Shan Vainio al.HNF1B proximal-intermediate identity vertebrates regulating signalling components Irx1/2.Development. 2013; 140: 873-885Crossref (97) Proximal–distal affected ligands, through proteolytic cleavage (35Cheng H.-T. Kim M.T. Surendran Schuster-Gossler Gossler al.Notch2, Notch1, acquisition mammalian nephron.Development. 134: 801-811Crossref (295) 36Duvall Crist Perl A.J. Shakked N.P. Chaturvedi Kopan Revisiting role notch segmentation selection during nephrogenesis.Development. 149dev200446Crossref (9) Sry-box containing Sox9 needed reactivated necessary (37Kang H.M. Huang Reidy Han S.H. Chinga F. Susztak Sox9-Positive play mice.Cell 14: 861-871Abstract (140) 38Kumar Liu Pang Krautzberger Reginensi Akiyama al.Sox9 pathway acutely kidney.Cell 1325-1338Abstract (156) 39Reginensi Clarkson Neirijnck Lu Ohyama Groves al.SOX9 activating RET effector development.Hum. Mol. Genet. 20: 1143-1153Crossref (110) An HNF4a network described appears (40Yoshimura Muto Omachi Miner J.H. Elucidating HNF4A organoids.J. 1672-1686Crossref (2) 41Marable S.S. Chung Park J.-S. Hnf4a Cdh6-Expressing 2543-2558Crossref (38) re-expressed upregulated (for details, Little Kairath, 2016 Scholar)), whether merely fully explored. level, regulated cis-acting DNA promoters enhancers trans-acting bind recruit RNA polymerase cofactors initiation elongation. Yet, context intact chromatin, consists DNA, histones, proteins. histones nucleosome post-translationally imprints, methylation acetylation lysine residues, determine accessibility machinery. Indeed, cell- tissue-specific modules solely specific histone (42Heintzman N.D. Stuart R.K. Hon G. Fu Ching C.W. Hawkins R.D. al.Distinct predictive signatures genome.Nat. 39: 311-318Crossref (2581) imprinted methyltransferases Trithorax Polycomb family Originally Drosophila activators embryonic expression, includes H3K4 methyltransferases, thought silence H3K27 H3K9. upregulate downregulate generally act upon accessible genome, epigenome, determined individual fates specified. ability quantify entire transcriptome revolutionized think about identity, plasticity. Hybridization microarrays was genome-wide scale. Next-generation bulk refined methods enable quantification mRNA splice variants precision economy. Moreover, become standard identifying new following pseudotime. Building decades mapped physiology disease, advanced bioinformatics beginning deconvolve complex high-resolution detail (43Badia-i-Mompel Wessels Müller-Dott Trimbour Flores R.O.R. Argelaguet al.Gene inference era multi-omics.Nat. 24: 1-16Crossref (52) addition measurements, direct mapping localization sequences scale progressed rapidly. Using antibodies against coupled next-generation (ChIP-Seq), binding profile across genome. Novel require less input material, under release using nuclease (CUT&RUN) tagmentation (CUT&Tag). extensive library publicly available ENCODE project (44Luo Hitz B.C. Gabdank Hilton Kagda Lam al.New developments Encyclopedia Elements (ENCODE) portal.Nucleic Acids Res. 2019; 48: D882-D889Crossref (299) becoming murine (45Wilflingseder Willi Lee H.K. Olauson Jankowski Ichimura al.Enhancer super-enhancer ischemic 11: 3383Crossref (59) (13Gisch samples. complement experimental computational approaches (46Weirauch Albu Cote A.G. Montenegro-Montero Drewe al.Determination Eukaryotic sequence specificity.Cell. 158: 1431-1443Abstract (1101) motifs factor–binding sites Independently, techniques measure transposase-accessible (ATAC-Seq) DNAse sensitivity hypersensitivity assays. show importantly, indicate open factors. Open regions contain combined networks. As RNA-Seq, scaled deployed use deep technology differential themselves (47Chang-Panesso Kadyrov F.F. Ikeda Kefaloyianni al.FOXM1 drives 129: 5501-5517Crossref (103) 48Kanamori Konno Osato Kawai Hayashizaki Suzuki nonredundant database.Biochem. Biophys. 2004; 322: 787-793Crossref 49Liu Sui Hofmann O.M. Chen Baetscher al.Cell-specific translational 124: 1242-1254Crossref (148) insufficient activity. Post-translational phosphorylation activity, stability, further given factor. overcome limitation, groups clustering (SCENIC) (50Aibar González-Blas C.B. Moerman Huynh-Thu V.A. Imrichova Hulselmans al.SCENIC: clustering.Nat. Methods. 1083-1086Crossref (2511) based activation. Briefly, approach correlates sets refines
Language: Английский
Citations
1
AJP Renal Physiology, Journal Year: 2024, Volume and Issue: 327(3), P. F397 - F411
Published: Sept. 1, 2024
Epigenetic mechanisms are considered to contribute diabetic nephropathy by maintaining memory of poor glycemic control during the early stages diabetes. However, DNA methylation changes in human kidney poorly characterized, because lack cell type-specific analysis. We examined proximal tubules (PTs) purified from patients with and identified differentially methylated CpG sites, given critical role injury. Hypermethylation was observed at sites annotated genes responsible for tubule functions, including gluconeogenesis, nicotinamide adenine dinucleotide synthesis, transporters glucose, water, phosphate, drugs, kidneys, whereas involved oxidative stress cytoskeleton exhibited demethylation. Methylation levels
Language: Английский
Citations
1