Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(16)

Опубликована: Авг. 14, 2022

With an aging population, kidney health becomes important medical and socioeconomic factor. Kidney mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor its 2 ligands (PD-L1 PD-L2). PDCD1 transcript with age in microdissected human glomeruli, which correlated lower estimated glomerular filtration rate higher segmental glomerulosclerosis vascular arterial intima-to-lumen ratio. In vitro studies demonstrated a critical role for PD-1 signaling survival the induction senescence-associated secretory phenotype. To prove was to podocyte aging, were injected anti–PD-1 antibody. Treatment significantly improved phenotype both liver. glomerulus, it life span podocytes, but parietal epithelial, mesangial, or endothelial cells. Transcriptomic immunohistochemistry antibody treatment podocytes. Administering same young experimental focal (FSGS) lowered proteinuria number. These results suggest contribution toward liver FSGS.

Язык: Английский

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Podocyte Aging: Why and How Getting Old Matters

Journal of the American Society of Nephrology, Год журнала: 2021, Номер 32(11), С. 2697 - 2713

Опубликована: Окт. 29, 2021

The effects of healthy aging on the kidney, and how these intersect with superimposed diseases, are highly relevant in context population's increasing longevity. Age-associated changes to podocytes, which terminally differentiated glomerular epithelial cells, adversely affect kidney health. This review discusses molecular cellular mechanisms underlying podocyte aging, might be augmented by disease aged approaches mitigate progressive damage podocytes. Furthermore, we address biologic pathways such as those associated growth confound humans rodents.

Язык: Английский

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Single cell landscape of parietal epithelial cells in healthy and diseased states

Kidney International, Год журнала: 2023, Номер 104(1), С. 108 - 123

Опубликована: Апрель 24, 2023

The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration crescent formation. Although protein markers have revealed the morphological heterogeneity PECs, molecular characteristics PEC subpopulations remain largely unknown. Here, we performed a comprehensive analysis PECs using single-cell RNA sequencing (scRNA-seq) data. Our identified five distinct subpopulations: PEC-A1, PEC-A2, PEC-A3, PEC-A4 PEC-B. Among these subpopulations, PEC- A1 PEC-A2 were characterized as progenitors while represented tubular progenitors. Further dynamic signaling network indicated that activation proliferation PEC-A3 played pivotal roles in Analyses suggested upstream signals released by podocytes, immune cells, endothelial mesangial serve pathogenic may be promising intervention targets crescentic glomerulonephritis. Pharmacological blockade two such targets, proteins Mif Csf1r, reduced hyperplasia formation anti-glomerular basement membrane glomerulonephritis murine models. Thus, our study demonstrates scRNA-seq-based provided valuable insights into pathology therapeutic strategies

Язык: Английский

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Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span

Aging, Год журнала: 2023, Номер 15(14), С. 6658 - 6689

Опубликована: Июль 23, 2023

Aging | doi:10.18632/aging.204897. Natalya Kaverina, R. Allen Schweickart, Gek Cher Chan, Joseph C. Maggiore, Diana G. Eng, Yuting Zeng, Sierra McKinzie, Hannah S. Perry, Adilijiang Ali, Christopher O’Connor, Beatriz Maria Veloso Pereira, Ashleigh B. Theberge, Joshua Vaughan, Carol J. Loretz, Anthony Chang, Neil A. Hukriede, Markus Bitzer, Jeffrey W. Pippin, Oliver Wessely, Stuart Shankland

Язык: Английский

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The Role of Parietal Epithelial Cells in the Pathogenesis of Podocytopathy

Frontiers in Physiology, Год журнала: 2022, Номер 13

Опубликована: Март 11, 2022

Podocytopathy is the most common feature of glomerular disorder characterized by podocyte injury- or dysfunction-induced excessive proteinuria, which ultimately develops into glomerulosclerosis and results in persistent loss renal function. Due to lack self-renewal ability podocytes, mild depletion triggers replacement repair processes mostly driven stem cells resident parietal epithelial (PECs). In contrast, when recovery fails, activated PECs contribute establishment lesions. Increasing evidence suggests that PECs, more than just bystanders, have a crucial role various podocytopathies, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, diabetic IgA lupus podocytopathy. this review, we attempt dissect diverse pathogenesis podocytopathy based on currently available information.

Язык: Английский

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PodoCount: A Robust, Fully Automated, Whole-Slide Podocyte Quantification Tool

Kidney International Reports, Год журнала: 2022, Номер 7(6), С. 1377 - 1392

Опубликована: Июнь 1, 2022

Podocyte depletion is a histomorphologic indicator of glomerular injury and predicts clinical outcomes. estimation methods or podometrics are semiquantitative, technically involved, laborious. Implementation high-throughput in experimental workflows necessitates an automated pipeline. Recognizing that computational image analysis offers robust approach to study cell tissue structure, we developed validated PodoCount (a tool for podocyte quantification immunohistochemically labeled tissues) using diverse data set.Whole-slide images (WSIs) tissues immunostained with nuclear marker periodic acid-Schiff counterstain were acquired. The set consisted murine whole kidney sections (n = 135) from 6 disease models human biopsy specimens patients diabetic nephropathy (DN) 45). Within segmented glomeruli, podocytes extracted was applied compute measures morphometry. Computational performance evaluation statistical testing performed validate podometric associated features. disbursed as open-source, cloud-based tool.PodoCount produced highly accurate when benchmarked against existing methods. profiles identified 0.98 accuracy 0.85 sensitivity 0.99 specificity. Errors count bounded by 1 per glomerulus. Podocyte-specific features found be significant predictors state, proteinuria, outcome.PodoCount high-performance quantitation specimens. Resultant offer correlation metadata outcome. Our will provide end users standardized gigapixel-sized WSIs.

Язык: Английский

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WT1⁺ glomerular parietal epithelial progenitors promote renal proximal tubule regeneration after severe acute kidney injury

Theranostics, Год журнала: 2023, Номер 13(4), С. 1311 - 1324

Опубликована: Янв. 1, 2023

Rationale: Mammalian renal proximal tubules can partially regenerate after acute kidney injury (AKI). However, cells participating in the tubule regeneration remain to be elucidated. Wilms' tumor 1 (WT1) expresses a subtype of glomeruli parietal epithelial (PECs) adult kidneys, it remains unclear whether these WT1+ PECs play role regeneration/repair AKI. Methods: Ischemia-reperfusion (IRI) mouse model was used investigate expression pattern WT1 severe Conditional deletion gene mice were generated using Pax8CreERT2 and WT1fl/fl examine function WT1. Then, genetic cell lineage tracing single-cell RNA sequencing performed illustrate that develop into tubular (PTECs). Furthermore, vitro clonogenicity, direct differentiation analysis vivo transplantation reveal stem cell-like properties PECs. Results: The protein PTECs increased aggravated via transient scattered stage, possess specific properties. Conclusions: We discovered group promote AKI, is essential for injury.

Язык: Английский

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Central role of podocytes in mediating cellular cross talk in glomerular health and disease

AJP Renal Physiology, Год журнала: 2024, Номер 326(3), С. F313 - F325

Опубликована: Янв. 11, 2024

Podocytes are highly specialized epithelial cells that surround the capillaries of glomeruli in kidney. Together with glomerular endothelial cells, these postmitotic responsible for regulating filtrate from circulating blood their organized network interdigitating foot processes wrap around basement membrane. Although podocyte injury and subsequent loss is hallmark many diseases, recent evidence suggests cell-cell communication between podocytes other nonglomerular critical development progression kidney disease. In this review, we highlight key cellular pathways how they might be a potential target therapy We also postulate serve as central hub under basal conditions response to stress, which may have implications diseases.

Язык: Английский

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(Zebra)fishing for nephrogenesis genes

Tissue Barriers, Год журнала: 2023, Номер 12(2)

Опубликована: Май 31, 2023

Kidney disease is a devastating condition affecting millions of people worldwide, where over 100,000 patients in the United States alone remain waiting for lifesaving organ transplant. Concomitant with surge personalized medicine, single-gene mutations, and polygenic risk alleles have been brought to forefront as core causes spectrum renal disorders. With increasing prevalence kidney disease, it imperative make substantial strides field genetics. Nephrons, functional units kidney, are epithelial tubules that act gatekeepers body homeostasis by absorbing secreting ions, water, small molecules filter blood. Each nephron contains series proximal distal segments explicit metabolic functions. The embryonic zebrafish provides an ideal platform systematically dissect genetic cues governing development. Here, we review use discover nephrogenesis genes.

Язык: Английский

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Single-cell lineage tracing approaches to track kidney cell development and maintenance

Kidney International, Год журнала: 2024, Номер 105(6), С. 1186 - 1199

Опубликована: Март 28, 2024

Язык: Английский

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