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| Open AccessLucerastat, an oral therapy for Fabry disease: results from a pivotal randomized phase 3 study and its open-label extension
Lucerastat was well-tolerated, but did not reduce neuropathic pain, abdominal pain, or diarrhea compared with placebo. Lucerastat reduced biomarkers of Fabry Disease at 6 months, and these reductions were maintained at the 18-month interim analysis.
- Peter Nordbeck
- , Ozlem Goker-Alpan
- & Derralynn Hughes
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Article
| Open Access
Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice
SGLT2 inhibitors lower blood glucose in patients with diabetes. Here, the authors report that fasting reduces renal expression of Sglt2 and glucose reabsorption by modulating circadian clock genes.
- Xiaoyue Pan
- , Cyrus Mowdawalla
- & M. Mahmood Hussain
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Article
| Open Access
The slit diaphragm in Drosophila exhibits a bilayered, fishnet architecture
The slit diaphragm is a key component of the glomerular filter. This study reveals that the slit diaphragm of Drosophila nephrocytes exhibits a fishnet architecture, offering insights into the molecular basis of renal filtration.
- Deborah Moser
- , Konrad Lang
- & Achilleas S. Frangakis
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Article
| Open Access
Prolonged glucagon exposure rewires lipid oxidation and drives diabetic kidney disease progression
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney failure. This study shows that prolonged glucagon exacerbates lipid accumulation, promoting renal injury in early DKD, rather than lipid oxidation. Targeting glucagon signaling significantly inhibits DKD progression.
- Xingfeng Liu
- , Jingwen Chen
- & Pingping Li
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Article
| Open Access
Physiologic Homeostasis in a Living Human after Pig Kidney Xenotransplantation
Kidney shortages limit treatment options for patients with end-stage kidney disease, prompting exploration of xenotransplantation. Here, the authors show that a genetically modified pig kidney sustained essential functions in a living human for 51 days, informing future clinical strategies.
- Sul A Lee
- , Marie-Camille Lafargue
- & Leonardo V. Riella
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| Open Access
Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice
Gasdermin E (GSDME) is abundantly expressed, but its physiological function remains unclear. Here, the authors show a non-pyroptotic function of GSDME in limiting renal inflammation during cisplatin nephrotoxicity by regulating O-GlcNAcylation and STAT3-S100A7A-RAGE signaling.
- Qingzhou Chen
- , Pengxiao Sun
- & Jing Nie
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Article
| Open Access
Normothermic human kidney preservation drives iron accumulation and ferroptosis
Ex vivo normothermic machine perfusion has been proposed to protect donor kidneys. Here, the authors show that red blood cell-based human kidney perfusion and associated hemolysis contribute to iron accumulation, ferroptosis, and kidney injury.
- Marlon J. A. de Haan
- , Marleen E. Jacobs
- & Ton J. Rabelink
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| Open Access
Impact of HLA evolutionary divergence and donor-recipient molecular mismatches on antibody-mediated rejection of kidney allografts
Kidney transplants are at risk of graft failure due to immune system rejection. Here, the authors assess a broad range of clinical and immunological baseline variables in a large, unselected kidney transplant cohort, providing further insights into factors associated with antibody-mediated rejection
- Zeynep Demir
- , Marc Raynaud
- & Alexandre Loupy
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| Open Access
In vitro generation of a ureteral organoid from pluripotent stem cells
The ureter is a tube that carries urine from the kidney to the bladder. Here, by elucidating the developmental signals involved in ureteral progenitors, the authors create ureteral organoids using mouse and human pluripotent stem cells.
- Yutaro Ibi
- , Koichiro Miike
- & Ryuichi Nishinakamura
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| Open Access
Three dimensional multiscalar neurovascular nephron connectivity map of the human kidney across the lifespan
The human kidney maintains homeostasis through a complex network of up to a million nephrons. Here the authors construct a 3D neuro-nephron connectivity map of human kidneys, which reveals neuro-glomerular communities across the kidney connected via “mother glomeruli” as hub points explaining structural basis for fluid homeostasis. These networks develop after birth and decline with age and in disease states
- Liam McLaughlin
- , Bo Zhang
- & Sanjay Jain
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| Open Access
The integrin repertoire drives YAP-dependent epithelial:stromal interactions during injury of the kidney glomerulus
Capillary loop architecture in the kidney glomerulus depends on epithelial-stromal interactions. Here the authors show that YAP and TAZ maintain capillary loop architecture and that kidney injury leads to shifts in the integrin repertoire that affect transcriptional activity of YAP and TAZ.
- Evelyne Huynh-Cong
- , Victoria Driscoll
- & Jordan A. Kreidberg
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| Open Access
Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids
AAVs show potential for kidney gene therapy, however, kidney gene transfer remains challenging. Here, the authors show that differing viral capsids exhibit distinct delivery to tubules and podocytes which is also dependent on injection routes, disease state and species.
- Taisuke Furusho
- , Ranjan Das
- & Hiroyuki Nakai
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Matters Arising
| Open Access
Reply to: Machine learning-driven virtual biopsy system may increase organ discards at aggressive kidney transplant centers
- Marc Raynaud
- , Gillian Divard
- & Alexandre Loupy
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Article
| Open Access
Non-invasive in vivo sensing of bacterial implant infection using catalytically-optimised gold nanocluster-loaded liposomes for urinary readout
Implant-associated infections with Staphylococcus aureus pose serious clinical challenges. Here, the authors develop a biosensor based on toxin-responsive liposomes encapsulating gold nanoclusters, providing a non-invasive, colourimetric diagnostic tool for bacterial infection detection with urinary readout.
- Kaili Chen
- , Adrian Najer
- & Molly M. Stevens
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| Open Access
Analyzing longitudinal trait trajectories using GWAS identifies genetic variants for kidney function decline
The authors use longitudinal data from the UK Biobank to search for genetic variants associated with kidney function decline. Using a linear mixed model, they identify 13 independent variants, incl. 6 novel, and link them to genetics of kidney aging.
- Simon Wiegrebe
- , Mathias Gorski
- & Iris M. Heid
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| Open Access
Normothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39
The authors previously reported that normothermic ex vivo kidney perfusion is superior to static cold storage in terms of organ protection, but the detailed mechanism was unclear. Here the authors show that the organ-protective effects of normothermic perfusion are mediated by maintenance of mitochondrial function and enhanced by administration of AP39, a mitochondria-targeted hydrogen sulfide donor.
- Masataka Kawamura
- , Catherine Parmentier
- & Lisa A. Robinson
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Article
| Open Access
Podocyte-specific KLF6 primes proximal tubule CaMK1D signaling to attenuate diabetic kidney disease
While diabetic kidney disease is characterized by initial glomerular injury, proximal tubule dysfunction determines the progression to kidney fibrosis. Here, the authors show that podocyte KLF6 attenuates proximal tubule injury via ApoJ-CaMK1D signaling in a murine model of diabetic kidney disease.
- Nehaben A. Gujarati
- , Bismark O. Frimpong
- & Sandeep K. Mallipattu
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Article
| Open Access
Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation
It is currently unknown how environmental cues regulate ciliary Polycystin ion channels on renal epithelial cells. Here authors identify a cilia-enriched oxysterol, 7β,27- dihydroxycholesterol (DHC), as a necessary activator of the polycystin complex
- Kodaji Ha
- , Nadine Mundt-Machado
- & Markus Delling
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Article
| Open Access
Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury
Deubiquitinating of key proteins may be involved in podocyte injury and diabetic kidney disease (DKD). Here, the authors show that OTUD5 in podocytes alleviates DKD through deubiquitinating TAK1 at the K158 site, preventing TAK1 phosphorylation and inflammatory responses in podocytes.
- Ying Zhao
- , Shijie Fan
- & Guang Liang
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Article
| Open Access
Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2
The renal epithelium is sensitive to changes in blood K+. Here, Zhang et al. identify low K+ as a potent activator of proximal tubule mTOR/AKT signaling, which occurs through the K+ channel, Kir4.2 to modulate epithelial cell growth and Na+ transport.
- Yahua Zhang
- , Fabian Bock
- & Andrew S. Terker
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Article
| Open Access
Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction
Siew et al. using multi-omic, physiological & imaging approaches have demonstrated that spaceflight causes kidney remodelling, suggesting a contribution to kidney stone formation, & that space radiation causes kidney damage & early signs of dysfunction.
- Keith Siew
- , Kevin A. Nestler
- & Stephen B. Walsh
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Article
| Open Access
Autophagy-deficient macrophages exacerbate cisplatin-induced mitochondrial dysfunction and kidney injury via miR-195a-5p-SIRT3 axis
Tubulointerstitial inflammation occurs frequently in acute kidney injury (AKI), and Mφ autophagy is a known contributor to inflammation-related diseases. Here, Yuan et al. show that Mφ autophagy deficiency induces systemic inflammation, impairs mitochondria, and worsens kidney injury in AKI mice.
- Yujia Yuan
- , Longhui Yuan
- & Yanrong Lu
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| Open Access
A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys
As demand for organ transplants exceeds availability there has been an unmet need to extend preservation of deceased donor kidneys. Here, the authors show that a cell-free nutrient-supplemented perfusate allows 4-day preservation of human kidneys using spatially resolved lipidomics and metabolomics.
- Marlon J. A. de Haan
- , Marleen E. Jacobs
- & Ton J. Rabelink
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Article
| Open Access
Enzymatic conversion of human blood group A kidneys to universal blood group O
ABO blood group compatibility restrictions limit the availability of organs for patients awaiting transplantation. Here, the authors show the rapid enzymatic removal of blood group A antigens from the vasculature of human kidneys using normothermic and hypothermic machine perfusion technologies to make universal blood group O organs for transplantation.
- Serena MacMillan
- , Sarah A. Hosgood
- & Michael L. Nicholson
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Article
| Open Access
The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration
In the kidney, maintaining permeability of the filtration barrier is critical. Here, Sachs W. et al show that homeostasis of podocytes and glomerular endothelial cells relies on differing proteasome constitutions which orchestrate endocytic activity in addition to protein degradation.
- Wiebke Sachs
- , Lukas Blume
- & Catherine Meyer-Schwesinger
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Article
| Open Access
High resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing
Advancements in spatial transcriptomics technologies have enabled the analysis of gene expression at cellular resolution in situ. The authors applied direct RNA hybridization-based in situ sequencing (dRNA HybISS) and developed a computational tool, CellScopes, to study gene expression in mouse kidneys, identifying cellular changes and interactions during injury and repair.
- Haojia Wu
- , Eryn E. Dixon
- & Benjamin D. Humphreys
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Article
| Open Access
Short-term hypercaloric carbohydrate loading increases surgical stress resilience by inducing FGF21
Surgery poses significant risks for patients, with attempts to mitigate these risks using multimodal perioperative care pathways. Here, the authors show that preoperative hypercaloric carbohydrate drinks not only alleviate surgical stress but also demonstrates the replicability of this protection using FGF21 treatment alone.
- Thomas Agius
- , Raffaella Emsley
- & Alban Longchamp
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| Open Access
Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing
Spatially resolved metabolism in complex tissues is vital but poorly understood. Here, the authors establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism at single-cell resolution to organ-wide physiology.
- Jack Holcombe
- & Helen Weavers
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Article
| Open Access
RAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis
Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) arises from mutations in Angiotensin II sensing genes, but how they impact the kidney was unclear. This study reveals that delayed angiogenesis at a critical developmental window underlies AR-RTD.
- Naomi Pode-Shakked
- , Megan Slack
- & Raphael Kopan
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Article
| Open Access
The AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells
Urinary flow is sensed by renal cells but its intensity is dysregulated in renal diseases. Here, the authors report that physiological flow inhibits YAP to promote autophagy, while pathological flow leads to YAP activation and autophagy inhibition.
- Aurore Claude-Taupin
- , Pierre Isnard
- & Nicolas Dupont
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Article
| Open Access
MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease
Cisplatin, a chemotherapy drug, can cause long-lasting kidney injury. The authors explore miRNA:mRNA interactions in cisplatin-injured kidneys and find that such a cisplatin inducible miRNA as miR-429-3p suppresses the catabolism of branched-chain amino acids, leading to stimulation of ferroptotic cell death.
- Hisakatsu Sone
- , Tae Jin Lee
- & Sang-Ho Kwon
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Article
| Open Access
Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance
Cell metabolism plays pivotal roles during kidney embryogenesis. This research shows that glycolysis modulation affects nephron progenitor cells via Acetyl-CoA-modulated pathways, influencing both kidney development, and nephron endowment at birth.
- Fabiola Diniz
- , Nguyen Yen Nhi Ngo
- & Giovane G. Tortelote
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Article
| Open Access
Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization
Adiponectin is a widely studied secretory protein produced by adipocytes. Here, the authors show that adiponectin is also expressed in the kidney where it is a major driver of fatty acid oxidation, from which the kidney derives energy for gluconeogenesis.
- Toshiharu Onodera
- , May-Yun Wang
- & Philipp E. Scherer
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Article
| Open Access
Proteomics of CKD progression in the chronic renal insufficiency cohort
Progression of chronic kidney disease may lead to kidney failure and cardiovascular, metabolic and bone disease complications. Here, the authors conduct a large-scale proteomic study in patients with chronic kidney disease, identify numerous proteins that predict kidney failure, some of which are likely causal mediators and hence potential therapeutic targets.
- Ruth F. Dubin
- , Rajat Deo
- & Peter Ganz
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Article
| Open Access
A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury in patients with stone disease
Kidney stone disease causes significant morbidity and increases in health care utilization. Here, the authors define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human renal papilla and identify associated urinary biomarkers.
- Victor Hugo Canela
- , William S. Bowen
- & Tarek M. El-Achkar
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Article
| Open Access
Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection
Although long-term kidney allograft failure is broadly classified as T cell- or antibody-mediated, this dichotomy is not always apparent in all patients, highlighting the need for improved allograft tissue characterisation. Here, the authors use single-cell RNA sequencing and multiplex imaging for transcriptomic and spatial profiling of allograft tissue from patients experiencing different degrees of rejection severity.
- Baptiste Lamarthée
- , Jasper Callemeyn
- & Maarten Naesens
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Article
| Open Access
A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury
KIM1 is dramatically upregulated in acute kidney injury (AKI) and but how KIM1 affects AKI remains unknown. Here, the authors report that renal specific Kim1 knockout relieves AKI, unveil a YY1-KIM1-DR5 axis in the progression of AKI, and suggest potential therapeutic strategies against AKI.
- Chen Yang
- , Huidie Xu
- & Ling Zheng
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Article
| Open Access
Signaling mechanisms in renal compensatory hypertrophy revealed by multi-omics
The authors used a multi-omic approach in a mouse unilateral nephrectomy model to identify signaling processes associated with compensatory hypertrophy of the renal proximal tubule. The results indicate that PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.
- Hiroaki Kikuchi
- , Chung-Lin Chou
- & Mark A. Knepper
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Article
| Open Access
Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation
Porcine kidney xenotransplantation is accelerating towards clinical testing. Here the authors present preclinical results examining xenograft growth and participation in renal endocrine pathways that can be used to inform clinical study design.
- Daniel J. Firl
- , Grace Lassiter
- & Katherine C. Hall
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Article
| Open Access
A previously uncharacterized Factor Associated with Metabolism and Energy (FAME/C14orf105/CCDC198/1700011H14Rik) is related to evolutionary adaptation, energy balance, and kidney physiology
The human genome still contains numerous uncharacterized genes. Here, the authors identify a fast evolving Factor associated with Metabolism and Energy (FAME) that is associated with altered body weight, energy expenditure, and metabolism and study its function in knockout mouse models.
- Julian Petersen
- , Lukas Englmaier
- & Igor Adameyko
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Article
| Open Access
The AE4 transporter mediates kidney acid-base sensing
Maintaining systemic acid-base balance is a central task of the kidneys, but it is still undetermined how acid-base alterations are perceived by the kidney. Here, the authors show that the solute transporter AE4 in β-intercalated cells is an essential part of the renal acid-base sensing mechanism
- H. Vitzthum
- , M. Koch
- & H. Ehmke
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Article
| Open Access
Isthmin-1 (Ism1) modulates renal branching morphogenesis and mesenchyme condensation during early kidney development
Loss of Ism1 in mice results in kidney agenesis and dysplasia that are common human diseases. Here they show that Ism1 is expressed in metanephric mesenchyme and acts as a ligand of Integrin α8β1 to regulate mesenchyme condensation during early renal branching morphogenesis.
- Ge Gao
- , Xiaoping Li
- & Zhongjun Zhou
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Article
| Open Access
The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion
Mutations in the gene encoding PC1 cause ADPKD, a common genetic renal disease. Here, the authors show that expression of the C-terminal 200 amino acids of the large PC1 protein in mouse models of ADPKD suppresses cystic disease through an interaction with the mitochondrial enzyme NNT.
- Laura Onuchic
- , Valeria Padovano
- & Michael J. Caplan
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Article
| Open Access
Clonal dynamics of alloreactive T cells in kidney allograft rejection after anti-PD-1 therapy
Immune checkpoint inhibitors (ICI) may have unanticipated side effects in transplant recipients who subsequently develop tumors. Here the authors used single-cell sequencing to identify and characterize allogeneic reactive T cells that developed after an ICI course for melanoma in a transplant recipient.
- Garrett S. Dunlap
- , Daniel DiToro
- & Deepak A. Rao
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Article
| Open Access
Increased levels of endogenous retroviruses trigger fibroinflammation and play a role in kidney disease development
The contribution of transposable elements and endogenous retroviruses to renal fibroinflammation is currently unknown. Here, the authors comprehensively profile the expression of transposable elements and endogenous retroviruses (ERVs) in kidneys of patients and mouse disease models and find expression of ERVs in diseased kidneys activate cytosolic nucleotide sensors contributing to cytokine release and renal fibroinflammation.
- Poonam Dhillon
- , Kelly Ann Mulholland
- & Katalin Susztak
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Article
| Open Access
Next-Generation Morphometry for pathomics-data mining in histopathology
Pathology diagnostics still rely on tissue morphology assessment by trained experts. Here, the authors perform deep-learning-based segmentation followed by large-scale feature extraction of histological images, i.e., next-generation morphometry, to enable outcome-relevant and disease-specific pathomics analysis of non-tumor kidney pathology.
- David L. Hölscher
- , Nassim Bouteldja
- & Peter Boor
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Article
| Open Access
Single-cell profiling of healthy human kidney reveals features of sex-based transcriptional programs and tissue-specific immunity
Knowledge of the transcriptional programs of human kidney cell populations at homeostasis is limited. Here, the authors show sex-based differences in gene expression of kidney parenchymal cells and examine the complexity of kidney-resident immune cells using single cell RNA sequencing of healthy living kidney donors.
- Caitriona M. McEvoy
- , Julia M. Murphy
- & Sarah Q. Crome
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Article
| Open Access
A slit-diaphragm-associated protein network for dynamic control of renal filtration
The slit-diaphragm is a cellular junction that is crucial for blood filtration in the kidney. Kocylowski et al. show that the junction-spanning components are embedded in a protein network for dynamic control of filtration; network disturbance leads to severe filtration defects with proteinuria.
- Maciej K. Kocylowski
- , Hande Aypek
- & Florian Grahammer
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Article
| Open Access
Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease
Acute kidney injury is frequent, often fatal and can leave survivors with chronic kidney disease. Here the authors show that tubular cell polyploidy reduces early fatality sustaining residual function but promotes chronic kidney disease, which can be prevented by blocking YAP1
- Letizia De Chiara
- , Carolina Conte
- & Paola Romagnani
Injured epithelial cell states impact kidney allograft survival after T-cell-mediated rejection