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| Open AccessA 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 AccessEnzymatic 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 AccessThe 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 AccessHigh 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 AccessShort-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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Article
| Open AccessFunctional-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 AccessRAAS-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 AccessThe 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 AccessMicroRNA-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 AccessAcetyl-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 AccessEndogenous 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 AccessProteomics 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 AccessA 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 AccessTranscriptional 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 AccessA 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 AccessSignaling 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 AccessClinical 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 AccessA 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 AccessThe 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 AccessIsthmin-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 AccessThe 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 AccessClonal 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 AccessIncreased 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 AccessNext-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 AccessSingle-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 AccessA 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 AccessTubular 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
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Article
| Open AccessSpatiotemporal organisation of protein processing in the kidney
Polesel et al. visualize plasma protein filtration, uptake and metabolism in the kidneys of living mice in real-time. They reveal coordinated activity of different specialized tubular segments, with major compensatory adaptations occurring in disease states.
- Marcello Polesel
- , Monika Kaminska
- & Andrew M. Hall
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Article
| Open AccessNanoscale segregation of channel and barrier claudins enables paracellular ion flux
Meshworks of claudin polymers control the paracellular transport and barrier properties of epithelial tight junctions. Here, the authors show different claudin nanoscale organization principles, finding that claudin segregation enables barrier formation and paracellular ion flux across tight junctions.
- Hannes Gonschior
- , Christopher Schmied
- & Martin Lehmann
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Article
| Open AccessImmune-mediated tubule atrophy promotes acute kidney injury to chronic kidney disease transition
Acute kidney injury can lead to chronic kidney disease. Here the authors show that the transition is related to a macrophage-mediated second wave of inflammatory cells that promote late tubule injury, dedifferentiation and fibrosis. Suppressing this second wave reduced tubular loss and kidney atrophy.
- Leyuan Xu
- , Jiankan Guo
- & Lloyd G. Cantley
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Article
| Open AccessAccelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension
Kidney metabolism in disease is important but not well understood. Here, using isotope-guided metabolomics, the authors show that lysine’s metabolic activity conveys kidney protection in hypertension through accelerated metabolism and physiological effects on tubular function.
- Markus M. Rinschen
- , Oleg Palygin
- & Alexander Staruschenko
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Article
| Open AccessSingle-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration
After acute injury, kidneys either successfully repair/regenerate or become fibrotic. Here the authors use scRNA-seq to study adaptive/maladaptive kidney regeneration and identify proinflammatory/fibrotic proximal tubule cells with pharmacologically targetable pyroptosis/ferroptosis signatures.
- Michael S. Balzer
- , Tomohito Doke
- & Katalin Susztak
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Article
| Open AccessKidney epithelial cells are active mechano-biological fluid pumps
How mechanical forces drive fluid transport in the kidney remains unclear. Here, the authors use a microfluidic platform to show that kidney epithelial cells generate hydraulic pressure gradients across the epithelium, and that the fluid flux is from apical to basal for normal cells, and inverted in autosomal dominant polycystic kidney disease cells.
- Mohammad Ikbal Choudhury
- , Yizeng Li
- & Sean X. Sun
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Article
| Open AccessOpposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function
Renal proximal tubules modulate whole-body homeostasis by sensing various nutrients. Here the authors describe the existence and importance of a unique CB1/mTORC1/GLUT2 signaling axis in regulating nutrient homeostasis in healthy and diseased kidney.
- Liad Hinden
- , Majdoleen Ahmad
- & Joseph Tam
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Article
| Open AccessLoss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease
Claudin-5 is a tight junction integral membrane protein, but it is also expressed in mature podocytes which lack tight junctions. Here the authors report that podocyte claudin-5 regulates WNT signaling activity by modulating WIF1 expression, and its downregulation contributes to kidney disease progression in mice.
- Hui Sun
- , Hui Li
- & Yongfeng Gong
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Article
| Open AccessGeneration of the organotypic kidney structure by integrating pluripotent stem cell-derived renal stroma
Organs consist of parenchyma and stroma. Nishinakamura and colleagues induce renal stromal progenitors from mouse pluripotent stem cells (PSCs), and generate completely PSC-derived organoids that reproduce complex kidney structure.
- Shunsuke Tanigawa
- , Etsuko Tanaka
- & Ryuichi Nishinakamura
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Article
| Open AccessInsulin-activated store-operated Ca2+ entry via Orai1 induces podocyte actin remodeling and causes proteinuria
Perturbations of Ca2+ signaling in podocytes may deteriorate kidney function and eventually lead to proteinuria. Here the authors show that insulin can affect the function of the calcium regulator Ora1 in podocytes, which is critical for maintaining kidney filter integrity.
- Ji-Hee Kim
- , Kyu-Hee Hwang
- & Seung-Kuy Cha
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Article
| Open AccessDysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury
Necroptosis, a form of cell death, occurs in acute renal injury. Here, the authors show that ferroptosis—a form of cell death dependent on iron - also occurs during acute kidney injury, and show that an inhibitor of ferroptosis can improve survival in a mouse model of acute kidney damage.
- Wulf Tonnus
- , Claudia Meyer
- & Andreas Linkermann
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Article
| Open AccessImportance of the renal ion channel TRPM6 in the circadian secretion of renin to raise blood pressure
Circadian variation of blood pressure, with higher values in the active period, is associated with the risk of fatal cardiovascular events. Here, we show the importance of renal TRPM6, a Magnesium-permeable cation channel, in raising blood pressure by stimulating renin secretion.
- Yosuke Funato
- , Daisuke Yamazaki
- & Hiroaki Miki
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Article
| Open AccessKidney intercalated cells are phagocytic and acidify internalized uropathogenic Escherichia coli
Kidney intercalated cells are involved in acid-base homeostasis in the kidneys. Here, the authors use single cell transcriptomics and find that interalated cells exhibit a transcriptional response conducive to defense and can engulf and acidify internalized bacteria, similarly to professional phagocytes.
- Vijay Saxena
- , Hongyu Gao
- & Andrew L. Schwaderer
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Article
| Open AccessSingle cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney
Single cell transcriptomic and epigenomic sequencing of human kidney highlight diverse cell types and states. These findings help characterize a novel population of injured proximal tubule cells and illustrate the power of multi-omic approaches to characterizing human tissue.
- Yoshiharu Muto
- , Parker C. Wilson
- & Benjamin D. Humphreys
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Article
| Open AccessSingle-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes
The molecular identity of renal glomerular cells is poorly characterized and rodent glomerulopathy models translate poorly to humans. Here, the authors show molecular signatures of glomerulus-associated cells using single cell RNA sequencing and highlight differences between mouse and human cells.
- Bing He
- , Ping Chen
- & Jaakko Patrakka
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Review Article
| Open AccessRenal metabolism and hypertension
Hypertension is one of the most important risk factors for cardiovascular disease. The kidneys, which have a very high metabolic rate, play a fundamental role in blood pressure regulation. In this review, the authors discuss recent studies on the role of renal metabolism in the development of hypertension.
- Zhongmin Tian
- & Mingyu Liang
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Article
| Open AccessDsbA-L mediated renal tubulointerstitial fibrosis in UUO mice
DsbA-L upregulation prevents lipid-induced renal injury in diabetic nephropathy. Here, the authors show that DsbA-L knockout attenuates tubulointerstitial fibrosis in mice, and show that this occurs via activation of Smad3 and p53, which result in modulation of CTGF, a regulator of kidney fibrosis.
- Xiaozhou Li
- , Jian Pan
- & Dongshan Zhang
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Article
| Open AccessInherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses
Salt levels in culture affect the polarisation of Th17 cells, which normally protect the host from fungal and bacterial infections. Here, the authors study patients with salt-losing tubulopathies (SLT) to find that, while Th17 immunity is dampened in SLT patients, their Th17-inducing signaling pathways are intact and can be reinvigorated by exogenous salt.
- Rhys D. R. Evans
- , Marilina Antonelou
- & Alan D. Salama
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Article
| Open AccessCyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo
Polycystic kidney disease (PKD) is characterized by the formation of large renal cysts, which lead to a decline in renal function. Here the authors show that genetic and chemical inhibition of TMEM16A largely reduces cyst enlargement in an in vivo model of autosomal dominant PKD.
- Ines Cabrita
- , Andre Kraus
- & Björn Buchholz
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Article
| Open AccessDisruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathology
Ketamine is a general anesthetic that is used also as an anti-depressant, but its use is associated with cystitis. Here, the authors show that ketamine is an antagonist of the Cav1.2 channel in bladder smooth muscle cells, that ablation of this channel in mice mimics the cystitis induced by ketamine, and show that this effect can be abrogated by an agonist of this ion channel.
- Huan Chen
- , David H. Vandorpe
- & Weiqun Yu
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Article
| Open AccessMolecular determinants of nephron vascular specialization in the kidney
The kidney is vascularized with highly specialized and zonated endothelial cells that are essential for its filtration function. Here, Barry et al. provide a single-cell RNA sequencing analysis of the kidney vasculature that highlights its transcriptional heterogeneity and uncovers pathways important for its development and function.
- David M. Barry
- , Elizabeth A. McMillan
- & Shahin Rafii
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Article
| Open AccessSingle cell census of human kidney organoids shows reproducibility and diminished off-target cells after transplantation
How reproducible human kidney organoids derived from different iPSC lines are, and how faithful they are to human kidney tissue remain unclear. Here, the authors use four human iPSC lines to derive kidney organoids and show how organoid composition is reproducible, comparable to human tissue and of improved quality after transplantation.
- Ayshwarya Subramanian
- , Eriene-Heidi Sidhom
- & Anna Greka