Collapsing Focal Segmental Glomerulosclerosis in Viral Infections

Frontiers in Immunology, Год журнала: 2022, Номер 12

Опубликована: Янв. 13, 2022

Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, collapsing form FSGS (cFSGS) is characterized by or global condensation and obliteration glomerular capillaries, appearance hyperplastic hypertrophic podocytes severe tubulointerstitial damage. Clinically, cFSGS patients present with acute injury, nephrotic-range proteinuria are at high risk rapid progression to irreversible failure. can be attributed numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein–Barr-Virus, parvovirus B19 also drugs ischemia. Risk variants APOL1 gene, predominantly found in people African descent, increase developing cFSGS. Patients infected new Corona-Virus SARS-CoV-2 display an increased rate injury (AKI) cases COVID-19. Besides hemodynamic instability, cytokine mediated direct entry infection renal epithelial cells contributing AKI, there emerging reports associated mainly ethnicity. The pathogenesis proposed linked podocytes, as described for HIV-associated glomerulopathy. Nevertheless, growing evidence that systemic inflammatory cascade, activated COVID-19, major contributor impairment basic cellular functions podocytes. This mini review will summarize current knowledge on focus influence immune responses potential mechanisms propagating development

Язык: Английский

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Autophagy as a Therapeutic Target for Chronic Kidney Disease and the Roles of TGF-β1 in Autophagy and Kidney Fibrosis

Cells, Год журнала: 2023, Номер 12(3), С. 412 - 412

Опубликована: Янв. 26, 2023

Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as aggregates, damaged organelles, and even invading pathogens. an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions has been linked to variety of biological processes disorders. It vital the homeostasis renal cells podocytes tubular epithelial cells, well immune healthy kidney. activation protects under stressed conditions, whereas autophagy deficiency increases vulnerability kidney injury, resulting several aberrant ultimately lead failure. Renal fibrosis condition that, if chronic, will progress end-stage disease, which at this point incurable. Chronic Kidney Disease (CKD) significant alterations signaling pleiotropic cytokine transforming growth factor-β1 (TGF-β1). While expression TGF-β1 can promote fibrogenesis, it also activate autophagy, suppresses tubulointerstitial fibrosis. complex impacts depending on context, types, pathological circumstances, be profibrotic or antifibrotic. Induction particularly proximal (PTECs) against stresses proteinuria-induced apoptosis ischemia-induced acute injury (AKI), loss scores increase sensitivity diseases. In review, we discuss new findings emphasize various functions producing not just but beneficial mechanisms autophagy.

Язык: Английский

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PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(15)

Опубликована: Июнь 6, 2024

Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There significant lack of effective treatment for these disorders. Here, following the identification somatic PIK3CA gain-of-function mutation in podocytes patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics crucial role played by this pathway proliferative development promoting podocyte proliferation, dedifferentiation inflammation. Additionally, show that alpelisib, PI3Kα inhibitor, improves glomerular lesions function different models lupus nephritis targeting podocytes. Surprisingly, determined pharmacological inhibition affects B T lymphocyte population with decrease production proinflammatory cytokines, autoantibodies complement deposition, which are all characteristic features PI3K delta (PI3Kδ) inhibition, primary isoform expressed lymphocytes. Importantly, does not impact under normal conditions. These findings were then confirmed human lymphocytes isolated from patients active nephritis. In conclusion, major condition, alpelisib acts on both immune system.

Язык: Английский

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Deep learning–based molecular morphometrics for kidney biopsies

JCI Insight, Год журнала: 2021, Номер 6(7)

Опубликована: Март 11, 2021

Morphologic examination of tissue biopsies is essential for histopathological diagnosis. However, accurate and scalable cellular quantification in human samples remains challenging. Here, we present a deep learning–based approach antigen-specific morphometrics kidney biopsies, which combines indirect immunofluorescence imaging with U-Net–based architectures image-to-image translation dual segmentation tasks, achieving human-level accuracy. In the kidney, podocyte loss represents hallmark glomerular injury can be estimated diagnostic biopsies. Thus, profiled over 27,000 podocytes from 110 samples, including patients antineutrophil cytoplasmic antibody–associated glomerulonephritis (ANCA-GN), an immune-mediated disease aggressive damage irreversible function. We identified previously unknown morphometric signatures depletion ANCA-GN, allowed patient classification and, combination routine clinical tools, showed potential risk stratification. Our enables robust molecular analysis tissues, yielding deeper biological insights into pathophysiology.

Язык: Английский

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Podocyte Autophagy in Homeostasis and Disease

Journal of Clinical Medicine, Год журнала: 2021, Номер 10(6), С. 1184 - 1184

Опубликована: Март 12, 2021

Autophagy is a protective mechanism that removes dysfunctional components and provides nutrition for cells. Podocytes are terminally differentiated specialized epithelial cells wrap around the capillaries of glomerular filtration barrier show high autophagy level at baseline. Here, we provide an overview cellular its regulation in homeostasis with specific reference to podocytes. We discuss recent data have focused on functional role during podocyte injury experimental clinical diseases. A thorough understanding could shed novel insights into survival mechanisms offer potential targets therapeutics disease.

Язык: Английский

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Oxyfluorfen exposure can cause acute kidney injury by promoting ROS-induced oxidative stress and inflammation in zebrafish

Journal of Hazardous Materials, Год журнала: 2022, Номер 440, С. 129823 - 129823

Опубликована: Авг. 24, 2022

Язык: Английский

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Roles of Hydrogen Sulfide Donors in Common Kidney Diseases

Frontiers in Pharmacology, Год журнала: 2020, Номер 11

Опубликована: Ноя. 19, 2020

Hydrogen sulfide (H 2 S) plays a key role in the regulation of physiological processes mammals. The decline H S level has been reported numerous renal disorders. In animal models disorders, treatment with donors could restore levels and improve functions. suppress dysfunction by regulating autophagy, apoptosis, oxidative stress, inflammation through multiple signaling pathways, such as TRL4/NLRP3, AMP-activated protein kinase/mammalian target rapamycin, transforming growth factor-β1/Smad3, extracellular signal-regulated kinases 1/2, mitogen-activated kinase, nuclear factor kappa B. this review, we summarize recent developments effects on common diseases, including acute/chronic kidney disease, fibrosis, unilateral ureteral obstruction, glomerulosclerosis, diabetic nephropathy, hyperhomocysteinemia, drug-induced nephrotoxicity, metal-induced urolithiasis. Novel can be designed applied diseases.

Язык: Английский

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Clearly imaging and quantifying the kidney in 3D

Kidney International, Год журнала: 2021, Номер 100(4), С. 780 - 786

Опубликована: Июнь 2, 2021

For decades, measurements of kidney microanatomy using 2-dimensional sections has provided us with a detailed knowledge morphology under physiological and pathological conditions. However, the rapid development tissue clearing methods in recent years, combination novel 3-dimensional imaging modalities have new insights into structure function. This review article describes range disease obtained recently these methodological approaches. example, developing approaches understandings ureteric branching morphogenesis, nephron progenitor cell proliferation commitment, interactions between tip cells cells, establishment segmentation. In whole adult mouse kidneys, combined light sheet microscopy can image quantify total number glomeruli, major breakthrough field. Similar renal vasculature innervation, tubulointerstitial remodeling, podocyte loss hypertrophy, cyst formation, evolution cellular crescents, glomerular filtration barrier. Many more advances understanding biology pathology be expected as additional techniques are developed adopted by investigators. Editor's NoteIn this review, which is part "Visualizing Techniques" series, discussed that very much facilitate reconstruction complex structures such tubules, particular tubular segments, or vasculature. What took weeks to months past now done rapidly thanks discovery smart combinations techniques. Total each normal human ranges from approximately 200,000 than 2 million,1Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human number: implications for health disease.Pediatr Nephrol. 2011; 26: 1529-1533Crossref PubMed Scopus (300) Google Scholar averaging 1 million. These nephrons well other components including collecting ducts, blood vessels, interstitia, nerve fibers arranged exquisite microanatomical precision.2Blanc T. Goudin N. Zaidan M. al.Three-dimensional architecture cystic kidney.Kidney Int. 2021; 99: 632-645Abstract Full Text PDF (3) precise patterning underpins function health, severely disturbed when altered due hypertrophy shrinkage, loss, congenital abnormalities, vessel rarefaction, interstitial fibrosis. A contributed our comprehensive during healthy diseased kidney. most part, come analysis (2D) whether they electron microscopic physical confocal optical sections. Quantitation mostly depended on stereological analyses estimates numbers, lengths, surface areas, volumes their components.3Bertram Analyzing glomeruli stereology.Int Rev Cytol. 1995; 161: 111-172Crossref (143) Scholar,4Nyengaard J.R. Stereologic application research.J Am Soc 1999; 10: 1100-1123Crossref Until recently, 3D visualization microstructure was largely limited microscopy, enables sectioning up depth 50 80 μm. Unfortunately, refractive properties protein lipid within scatter dramatically reduce quality increases. been remove pigment content match mounting media render transparent.5Puelles V.G. Moeller M.J. Bertram We see clearly now: morphometrics.Curr Opin Nephrol Hypertens. 2017; 179-186Crossref (11) Clearing complexity incubating various solutions over period hours extended procedures involving custom electrochemical equipment. direct readers reviews5Puelles Scholar,6Ueda H.R. Erturk A. Chung K. al.Tissue its applications neuroscience.Nat Neurosci. 2020; 21: 61-79Crossref (184) overview current methods, papers cited herein specific use cases. Subcellular entire populations resolved cleared organs thick Accurately features requires specialized microscopes processing capture reconstruct volumetric data samples hundreds microns centimeters size. Point scanning spinning disk effectively used but suffer reduced resolution Z axis progressive reduction fluorescence intensity at single illumination imaging. Light particularly suited tissues enable fast acquisition large include multiangle Optical projection tomography another approach incorporates digital produce X, Y, axes voxel same resolution. Regardless approach, mount provide opportunity explore uncharted microenvironments higher-order structure. we highlight some development, structure, resulted followed quantitative analysis. Decades gene expression profiling knockout studies led types, regulatory networks, signaling pathways control mammalian development. informed diagnosis enabled production types pluripotent stem cells.7Little M.H. Combes A.N. Kidney organoids: accurate models fortunate accidents.Genes Dev. 2019; 33: 1319-1345Crossref (57) size, opacity, presented significant barrier precisely measuring morphogenesis organ distribution proteins it. The multiscale populations, endowment intact (Figure 1).8Short Hodson Smyth I. Spatial mapping quantification developmental morphogenesis.Development. 2013; 140: 471-478Crossref (66) underpin capacity precision phenotyping open avenues analyze molecular drivers disease. Establishment tree defining feature extensively studied genetics flattened explant cultures. how individual genes contribute growth, form, branched epithelial duct vivo required network across wide sample sizes. Short al.8Short addressed issues immunofluorescence, solvent-based (benzyl alcohol–benzyl benzoate) tomography. Employing snapshots early mid-kidney team software derive unprecedented detail about number, branch angles length, volumes, generations trees 1c d).8Short Initially characterize identify aspects branching,9Combes K.M. Lefevre J. al.An integrated pipeline multidimensional morphogenesis.Nat Protoc. 2014; 9: 2859-2879Crossref (28) Scholar,10Short al.Global dynamics kidney.Dev Cell. 29: 188-202Abstract (175) ongoing efforts seek define principles key regulators govern vivo.11Lefevre J.G. Lamberton T.O. al.Branching governed rules pattern tree.Development. 144: 4377-4385PubMed Molecular play role establishing complement life. Uninduced progenitors factors promote growth through while spatially restricted cues both maintain state induce subset differentiate an nephron. drive cycle induction ceases around birth, remaining differentiate. Prior relative abundance time limited. changed utilizing immunofluorescence protocols, clearing, (confocal) level (optical tomography, sheet).9Combes It became apparent rates vary initially declining phases correlate reductions nephrogenic niche.10Short Three-dimensional fetal kidneys (week 11) cortex (weeks 11–23) affirm decrease niche size conserved species.12Lindstrom N.O. McMahon J.A. Guo al.Conserved divergent organogenesis.J 2018; 785-805Crossref (109) Further comparative time-based recruitment model wherein progressively added adopt segment identity according order arrive.13Lindstrom De Sena Brandine G. Tran al.Progressive mesenchymal reveals time-dependent process fate nephrogenesis.Dev 45: 651-660e4Abstract (94) study focused hydrogel-based method (passive Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging/Immunostaining/In situ hybridization-compatible Tissue-hYdrogel [CLARITY]14Yang Treweek J.B. Kulkarni R.P. al.Single-cell transparent whole-body clearing.Cell. 158: 945-958Abstract (611) Scholar) ability retain endogenous tdTomato reporter. Analysis tdTomato-labeling showed committing return state, where prior results suggested commitment unidirectional.15Lawlor K.T. Zappia L. al.Nephron stochastic influenced migration.Elife. 8e41156Crossref (29) Thus, improved dynamic processes scales species. Advances phenotyping. Statistically robust changes identified subtle phenotypes Ret+/− Six2+/− mice 2), were previously classified "normal."10Short Scholar,16Combes Wilson S. Phipson al.Haploinsufficiency Six2 increases promoting number.Kidney 93: 589-598Abstract (17) High-resolution Wnt11−/− phenotype appear disorganized inability form stable attachments prematurely differentiate.17O'Brien L.L. al.Wnt11 directs polarity motile behavior ultimately determining endowment.Elife. 7e40392Crossref also DNA methyltransferase 1, microRNAs Lin28 Let7, TSC1 influence number.18Volovelsky O. Nguyen Jarmas A.E. al.Hamartin regulates cessation nephrogenesis independently Mtor.Proc Natl Acad Sci U S 115: 5998-6003Crossref (19) Scholar, 19Wanner Vornweg al.DNA controls renewal differentiation.J 30: 63-78Crossref (36) 20Yermalovich A.V. Osborne J.K. Sousa P. al.Lin28 Let-7 regulate timing murine nephrogenesis.Nat Commun. 168Crossref Precision likely become important tool effort understand additive effect genetic environmental low predisposition chronic being produced fueling wave image-based mathematical modeling attempts discern macroscopic arise populations.11Lefevre Scholar,21Hannezo E. Scheele C. Moad al.A unifying theory morphogenesis.Cell. 171: 242-255e27Abstract (80) 22Menshykau D. Michos Lang al.Image-based GDNF-RET based Turing-type mechanism pattern-modulating WNT11 feedback.Nat 239Crossref (40) 23Zubkov V.S. spatially-averaged morphogenesis.J Theor Biol. 2015; 379: 24-37Crossref (16) will critical may hold improving accuracy intricate limits 2D morphological tools convey incomplete misleading perceptions Here, discuss years allow kidney, ranging all way 3).24Klingberg Hasenberg Ludwig-Portugall al.Fully automated evaluation capillary tuft nephritic lightsheet microscopy.J 28: 452-459Crossref (178) 25Østergaard M.V. Sembach F.E. Skytte J.L. al.Automated diabetic nephropathy.Kidney360. 6: 469-479Crossref 26Hasegawa Susaki E.A. Tanaka al.Comprehensive three-dimensional (CUBIC-kidney) visualizes abnormal sympathetic nerves after ischemia/reperfusion injury.Kidney 96: 129-138Abstract (23) 27Puelles van der Wolde J.W. Schulze K.E. al.Validation counting sizing podocytes glomeruli.J 2016; 27: 3093-3104Crossref 28Puelles Fleck Ortz al.Novel documents glomerulonephritis.Kidney 505-516Abstract 29Unnersjo-Jess Butt Hohne simple swelling protocol in-situ scales.Kidney 1010-1020Abstract shows high intra- intersubject variability volume, described autopsy subjects without overt diseases1Bertram Scholar,30Puelles Hoy W.E. Hughson M.D. al.Glomerular risk disease.Curr 20: 7-15Crossref (102) Scholar,31Puelles Zimanyi M.A. Samuel al.Estimating volume kidney: clinical perspectives.Nephrol Dial Transplant. 2012; 1880-1888Crossref (30) linked disturbances. gold standard experimental disector/fractionator method, design-based method.3Bertram While precise, it hands-on, time-consuming, training. reason, alternative proposed devise efficient high-quality endpoints:32Puelles Counting podocytes: rationale methodologies.Curr 24: 224-230PubMed hydrophobic (previously known solvent-based), hydrophilic hydrogel-based, advanced (e.g., confocal, multiphoton, sheet). To knowledge, first report published Klingberg al.24Klingberg landmark paper featured multiple advances. First, introduced ethyl cinnamate, nonhazardous solvent could replace toxic chemicals benzyl benzoate, until then regularly protocols. Second, investigators performed aggressive immune-mediated disease, identifying course. addition, steps toward computerized automation segmentation algorithms introduced, providing path efficiency improvements. Recently, Østergaard al.25Østergaard similar provides nephropathy. Furthermore, elegant functional labeling proximal tubuli via albumin injection visualize glomerular-tubular juncture correlative histopathology optically samples. flexibility becoming multilayered pipelines profiling. Following tracks almost impossible conventional histology structural extensive expert serial sectioning. Huang al.33Huang Brenna Khan A.U.M. cationic near infrared fluorescent agent ethyl-cinnamate vascular staining imaging.Sci Rep. 521Crossref (20) reported dye (MHI148-PEI) specifically label modified accelerated cinnamate shorten time. opens research especially high-resolution required. Similarly, Hasegawa al.26Hasegawa Unobstructed Brain/Body Imaging Cocktails Computational (CUBIC) together custom-built system innervation Sympathetic primarily distributed arteries. After 10 days ischemia reperfusion injury, density significantly decreased, correlating norepinephrine levels tissue. partially persisted 28 initial suggesting continuous alterations found progression difficult 3D. convoluted poses challenges microscopy. allows surrounding microenvironment. Saritas al.34Saritas Puelles Su X.T. al.Optical potassium-mediated tubule remodeling.Cell 25: 2668-2675e3Abstract (26) semiautomatic distal remodeling dietary potassium deprivation. quantified hyperplasia detected increase proliferating tubulointerstitium. utilized versatility perform hydrogel-embedding single-cell slices better question. Combinations Tahaei al.35Tahaei Coleman R. al.Distal sexual dimorphism revealed imaging.Am J Physiol Renal Physiol. 319: F754-F764Crossref (9) who characterized length tubule, determine adapt stress, Schuh al.36Schuh C.D. Polesel Platonova al.Combined axial differences endocytosis.J 2696-2712Crossref (34) ligand uptake endolysosomal function, highlighting S1 highly reabsorb receptor-mediated endocytosis. study, Blanc al.2Blanc analyzed showing cysts only determined shape located contiguous nondilated tubules. Overall, examples systematic compartment. glomerulus unique example units organ. particular, depletion directly benefited technological methodologies require investment resources.37Puelles Cullen-McEwen al.Design-based estimating numbers podocytes.Ann Anat. 196: 48-56Crossref (15) morphometric immunolabeling indirect facilitated volume. believe ideal affect leading focal segmental glomerulosclerosis).27Puelles technique later applied compensatory response following mediated target rapamycin pathway.38Puelles Wanner al.mTOR-mediated integrity humans.JCI Insight. 4e99271Crossref podocytes, any type spatial Another needed successfully toolbox morphometry lineage tracing. Most tend certain degree quenching (which varies mild severe).6Ueda combines tracing, multiphoton parietal activation.28Puelles crescentic nephritis metabolic enhanced green protein. crescents visualized migration marked tracked course nephritis. allowed identification lesion progressed occlusions formation atubular glomeruli. paves future immune-epithelial kidneys. An diagnostic routine assessment diseases ultrastructural biopsies field expansion definition aims increasing dimensions. Over Unnersjo-Jess al.39Unnersjo-Jess Scott Blom H. Brismar Super-resolution stimulated emission slit diaphragm tissue.Kidney 89: 243-247Abstract (52) Scholar,40Unnersjo-Jess Sevilla S.Z. al.Confocal super-resolution expansion.Kidney 1008-1013Abstract protocols nanoscale procedure morphology, combining concepts resolve microscopy.29Unnersjo-Jess pathologic foot effacement, basement membrane, IgG deposits, classical glomerulosclerosis, fibrosis, atrophy). summary, accessible tools. scalability implementation practice need equipment spectrum includes implemented laboratories improve commonly available microscopes. As opportunities afforded apparent, anticipate wider systems tailored workflows address questions. neuroscience served testing ground applications. Automated analysis, studying connectivity, tissue-wide atlas projects context. yield anatomy interdependency

Язык: Английский

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Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH

JCI Insight, Год журнала: 2023, Номер 8(1)

Опубликована: Янв. 9, 2023

A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) has been suggested, but which polarization state these characterizes this and development fibrosis remain unclear. In addition, a gut-liver axis suggested play in NASH, just begun be investigated. Combining single-cell RNA sequencing multiple-parameter flow cytometry, we provide first cell atlas our knowledge focused on liver-infiltrating patients with NAFLD showing that NASH is characterized by population multicytokine-producing cells. Among cells, only those Th17 were enriched advanced fibrosis. parallel, observed Bacteroides appeared intestine correlate frequency short, deliver providing rationale target block development. Finally, data offer an early indication test whether are part characterizing NASH.

Язык: Английский

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State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Июль 12, 2023

Nephrotic syndrome (NS) is a clinical entity characterized by proteinuria, hypoalbuminemia, and peripheral edema. NS affects about 2–7 per 100,000 children aged below 18 years old yearly classified, based on the response to drugs, into steroid sensitive (SSNS), dependent, (SDNS), multidrug dependent (MDNS), resistant (MRNS). Forms of that are more difficult treat associated with worse outcome respect renal function. In particular, MRNS commonly progresses end stage failure requiring transplantation, recurrence original disease in half cases. Histological presentations may vary from minimal glomerular lesions (MCD) focal segmental glomerulosclerosis (FSGS) and, relevance, histological patterns do not correlate treatments. Moreover, around cases secondary causative pathogenic variants genes involved maintaining structure. The pathogenesis still poorly understood therapeutic approaches mostly experience. Understanding pathogenetic mechanisms one ‘unmet needs’ nephrology represents significant challenge for scientific community. scope present review includes exploring relevant findings, identifying unmet needs, reviewing developments characterize last decades. main aim provide basis new perspectives mechanistic studies NS.

Язык: Английский

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