Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment
. Less than half ...of all patients respond to the primary treatment for PDAC, chemotherapy
, and genetic alterations alone cannot explain this
. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.
Multiorgan and Renal Tropism of SARS-CoV-2 Puelles, Victor G; Lütgehetmann, Marc; Lindenmeyer, Maja T ...
New England journal of medicine/The New England journal of medicine,
08/2020, Letnik:
383, Številka:
6
Journal Article
SARS-CoV-2-mediated acute kidney injury might be explained by indirect factors (eg, cytokine-mediated injury) and by direct viral infection and replication in kidney epithelial cells.4 We isolated ...SARS-CoV-2 from an autopsied kidney, which produced a 1000-times increase in viral RNA after 48 h of cell infection in vitro (figure; appendix p 1), thus confirming the presence of infective virus in the kidney, even under post-mortem conditions. Furthermore, we found that patient-derived SARS-CoV-2 replicates in non-human primate kidney tubular epithelial cells (the main cellular target of acute kidney injury) using indirect immunofluorescence imaging of SARS-CoV-2 non-structural protein 3, one of the SARS-CoV replicase cleaving products (appendix p 5).5 Our findings indicate that SARS-CoV-2 renal tropism is associated with disease severity (ie, premature death) and development of acute kidney injury. TBH reports grants from the German Research Foundation (CRC/1192, HU 1016/8-2, HU 1016/11-1, HU 1016/12-1), the Federal Ministry of Education and Research (STOP-FSGS-01GM1518C), and the European Research Council (grant 616891) during the study; grants and personal fees from Fresenius Medical Care; grants from Amicus Therapeutics and Sanofi Genzyme; and personal fees from Boehringer Ingelheim, Goldfinch Bio, Novartis Pharma, DaVita Germany, and Bayer Vital, unrelated to this Correspondence.
Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist
. The origin, functional heterogeneity and regulation of scar-forming cells ...that occur during human kidney fibrosis remain poorly understood
. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis.
The cellular responses induced by mitochondrial dysfunction remain elusive. Intrigued by the lack of almost any glomerular phenotype in patients with profound renal ischemia, we comprehensively ...investigated the primary sources of energy of glomerular podocytes. Combining functional measurements of oxygen consumption rates, glomerular metabolite analysis, and determination of mitochondrial density of podocytes in vivo, we demonstrate that anaerobic glycolysis and fermentation of glucose to lactate represent the key energy source of podocytes. Under physiological conditions, we could detect neither a developmental nor late-onset pathological phenotype in podocytes with impaired mitochondrial biogenesis machinery, defective mitochondrial fusion-fission apparatus, or reduced mtDNA stability and transcription caused by podocyte-specific deletion of Pgc-1α, Drp1, or Tfam, respectively. Anaerobic glycolysis represents the predominant metabolic pathway of podocytes. These findings offer a strategy to therapeutically interfere with the enhanced podocyte metabolism in various progressive kidney diseases, such as diabetic nephropathy or focal segmental glomerulosclerosis (FSGS).
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•Anaerobic glycolysis represents the predominant energy source of podocytes•Neither mitochondrial turnover nor mtDNA transcription impairs podocyte function•These findings elucidate podocyte metabolism, function, and glomerular integrity
Glomerular podocytes form the third and most outer layer of the kidney filtration barrier responsible for restricting the passage of proteins into the urine. Brinkkoetter et al. show that podocyte metabolism primarily relies on anaerobic glycolysis and the fermentation of glucose to lactate.
Recent studies have reported a variety of urine abnormalities in patients hospitalized due to severe acute respiratory syndrome coronavirus 2 infection. In a single-center study from Belgium, Werion ...et al. present a concise investigation of tubular dysfunction in patients with coronavirus disease 2019, identifying potential risk factors for increased disease severity. These data complement current evidence regarding severe acute respiratory syndrome coronavirus 2 presence and potential infection in the kidney.
Clearly imaging and quantifying the kidney in 3D Puelles, Victor G.; Combes, Alexander N.; Bertram, John F.
Kidney international,
October 2021, 2021-10-00, 20211001, Letnik:
100, Številka:
4
Journal Article
Recenzirano
Odprti dostop
For decades, measurements of kidney microanatomy using 2-dimensional sections has provided us with a detailed knowledge of kidney morphology under physiological and pathological conditions. However, ...the rapid development of tissue clearing methods in recent years, in combination with the development of novel 3-dimensional imaging modalities have provided new insights into kidney structure and function. This review article describes a range of novel insights into kidney development and disease obtained recently using these new methodological approaches. For example, in the developing kidney these approaches have provided new understandings of ureteric branching morphogenesis, nephron progenitor cell proliferation and commitment, interactions between ureteric tip cells and nephron progenitor cells, and the establishment of nephron segmentation. In whole adult mouse kidneys, tissue clearing combined with light sheet microscopy can image and quantify the total number of glomeruli, a major breakthrough in the field. Similar approaches have provided new insights into the structure of the renal vasculature and innervation, tubulointerstitial remodeling, podocyte loss and hypertrophy, cyst formation, the evolution of cellular crescents, and the structure of the glomerular filtration barrier. Many more advances in the understanding of kidney biology and pathology can be expected as additional clearing and imaging techniques are developed and adopted by more investigators.
Optical tissue transparency permits scalable cellular and molecular investigation of complex tissues in 3D. Adult human organs are particularly challenging to render transparent because of the ...accumulation of dense and sturdy molecules in decades-aged tissues. To overcome these challenges, we developed SHANEL, a method based on a new tissue permeabilization approach to clear and label stiff human organs. We used SHANEL to render the intact adult human brain and kidney transparent and perform 3D histology with antibodies and dyes in centimeters-depth. Thereby, we revealed structural details of the intact human eye, human thyroid, human kidney, and transgenic pig pancreas at the cellular resolution. Furthermore, we developed a deep learning pipeline to analyze millions of cells in cleared human brain tissues within hours with standard lab computers. Overall, SHANEL is a robust and unbiased technology to chart the cellular and molecular architecture of large intact mammalian organs.
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•CHAPS forms smaller micelles allowing full permeabilization of aged human organs•SHANEL enables centimeters deep molecular labeling and clearing of whole human organs•SHANEL renders intact adult human brain and kidney transparent•Deep learning and light-sheet microscopy with SHANEL allows human organ mapping
Zhao et al. present an approach for intact human organ mapping that uses a new tissue permeabilization method to clear and deeply label whole organs followed by light-sheet microscopy imaging and a deep learning-based pipeline for 3D reconstruction and data analysis.
Crescentic glomerulonephritis represents a group of kidney diseases characterized by rapid loss of kidney function and the formation of glomerular crescents. While the role of the immune system has ...been extensively studied in relation to the development of crescents, recent findings show that parietal epithelial cells play a key role in the pathophysiology of crescent formation, even in the absence of immune modulation. This review highlights our current understanding of parietal epithelial cell biology and the reported physiological and pathological roles that these cells play in glomerular lesion formation, especially in the context of crescentic glomerulonephritis.
Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by ...supporting antibody production and phagocytosis. In particular, Th1 and Th17 cells secreting IFN-γ and IL-17A, are involved in the control of systemic S. aureus infections in humans and mice. To investigate the role of T cells in severe S. aureus infections, we established a mouse sepsis model in which the kidney was identified to be the organ with the highest bacterial load and abundance of Th17 cells. In this model, IL-17A but not IFN-γ was required for bacterial control. Using Il17aCre × R26YFP mice we could show that Th17 fate cells produce Th17 and Th1 cytokines, indicating a high degree of Th17 cell plasticity. Single cell RNA-sequencing of renal Th17 fate cells uncovered their heterogeneity and identified a cluster with a Th1 expression profile within the Th17 cell population, which was absent in mice with T-bet/Tbx21-deficiency in Th17 cells (Il17aCre x R26eYFP x Tbx21-flox). Blocking Th17 to Th1 transdifferentiation in Th17 fate cells in these mice resulted in increased S. aureus tissue loads. In summary, we highlight the impact of Th17 cells in controlling systemic S. aureus infections and show that T-bet expression by Th17 cells is required for bacterial clearance. While targeting the Th17 cell immune response is an important therapeutic option in autoimmunity, silencing Th17 cells might have detrimental effects in bacterial infections.
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