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| Open AccessA plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity
Autoreactivity to myeloperoxidase (MPO) causes autoimmune vasculitis and severe glomerulonephritis. Here, Ooi et al. show that a Staphylococcus aureus plasmid encodes a peptide that is homologous to an immunodominant MPO epitope and induces anti-MPO autoimmunity and glomerulonephritis in mice.
- Joshua D. Ooi
- , Jhih-Hang Jiang
- & A. Richard Kitching
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| Open AccessThe tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression
In both focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN), kidney injury is characterised by the invasion of glomerular tufts by parietal epithelial cells (PECs). Here Lazareth et al. identify the tetraspanin CD9 as a key regulator of PEC migration, and find its upregulation in FSGS and CGN contributes to kidney injury in both diseases.
- Hélène Lazareth
- , Carole Henique
- & Pierre-Louis Tharaux
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| Open AccessA single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys
Single-cell studies in solid tissues remain challenging and have benefited from the development of single-nuclei RNA sequencing strategies. Here Lake et al. apply single-nucleus RNA sequencing to human kidney tissues to provide a comprehensive molecular and cellular atlas of the human kidney, with potential implications for the understanding of kidney physiology and disease.
- Blue B. Lake
- , Song Chen
- & Sanjay Jain
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| Open AccessKidney cytosine methylation changes improve renal function decline estimation in patients with diabetic kidney disease
Patients with diabetes commonly develop diabetic kidney disease (DKD). Here Gluck et al. identify a set of probes differentially methylated in renal samples from patients with DKD, and find that inclusion of these methylation probes improves current prediction models of renal function decline.
- Caroline Gluck
- , Chengxiang Qiu
- & Katalin Susztak
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| Open AccessCirculating miR-103a-3p contributes to angiotensin II-induced renal inflammation and fibrosis via a SNRK/NF-κB/p65 regulatory axis
Angiotensin II is known to cause renal inflammation and fibrosis. Here Lu et al. show that levels of circulating miR-103a-3p are elevated in hypertensive nephropathy patients and in an animal model of angiotensin II-induced renal dysfunction, and that miR-103a-3p suppresses SNRK expression leading to the activation of the pro-inflammatory NF-κB pathway in glomerular endothelial cells.
- Qiulun Lu
- , Zejun Ma
- & Ming-Hui Zou
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| Open AccessDisruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity
Kinase inhibitors used in chemotherapy are known for their adverse effects on kidney physiology. Here, Calizo et al. show that dasatinib is associated with a higher risk of glomerular toxicity compared to other kinase inhibitors, due to deleterious effects on cytoskeletal biomechanics in podocytes.
- Rhodora C. Calizo
- , Smiti Bhattacharya
- & Evren U. Azeloglu
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| Open AccessTMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells
Polycystin-2 (PC2) is an ion channel commonly found mutated in autosomal dominant polycystic kidney disease. Here Arhatte et al. identify transmembrane protein 33 (TMEM33) as a regulator of PC2 function at the endoplasmic reticulum, and find that deletion of TMEM33 protects mice from acute kidney injury.
- Malika Arhatte
- , Gihan S. Gunaratne
- & Amanda Patel
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| Open AccessSex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis
Estimated glomerular filtration rate (eGFR) is a measure of kidney function and used to characterize chronic kidney disease. Here, Graham et al. identify 53 novel loci for eGFR in a GWAS meta-analysis, a subset of which are associated with other common diseases, such as diabetes and hypertension, based on PheWAS.
- Sarah E. Graham
- , Jonas B. Nielsen
- & Cristen J. Willer
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| Open AccessGut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease
Diabetes is a major cause of kidney disease. Here Kikuchi et al. show that phenol sulfate, a gut microbiota-derived metabolite, is increased in diabetic kidney disease and contributes to the pathology by promoting kidney injury, suggesting phenyl sulfate could be used a marker and therapeutic target for the treatment of diabetic kidney disease.
- Koichi Kikuchi
- , Daisuke Saigusa
- & Takaaki Abe
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| Open AccessIdentification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan
Accurate monitoring of chronic kidney disease (CKD) progression is essential for efficient disease management. Here Chen et al. identify five serum metabolites in patients with stage 1–5 CKD whose levels associate with disease progression, and find that 5-methoxytryptophan and its regulatory enzyme TPH-1 exert anti-fibrotic effects in mouse models of kidney injury.
- Dan-Qian Chen
- , Gang Cao
- & Ying-Yong Zhao
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Article
| Open AccessPoly(ADP-ribose) polymerase 1 accelerates vascular calcification by upregulating Runx2
Vascular calcification is a hallmark of end stage renal disease. Here, Cheng et al. show that poly(ADP-ribose) polymerase (PARP) activity is increased in calcified arteries in patients and uremic rats, and that PARP1 promotes vascular calcification by suppressing miR-204 expression via IL-6/STAT3 signaling, thus relieving repression of the osteogenic regulator Runx2.
- Cheng Wang
- , Wenjing Xu
- & Kai Huang
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| Open AccessA late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation
Allograft can induces local chronic inflammation, but how this feeds back to regulating late immunity is still not clear. Here the authors show, by charactering B cell transcriptome landscape dynamic in human allografts and in mouse kidneys transitioning from acute to chronic injury, that late B cell activation is associated with renal dysfunction and inflammation.
- Pietro E. Cippà
- , Jing Liu
- & Andrew P. McMahon
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| Open AccessPodocyte GSK3 is an evolutionarily conserved critical regulator of kidney function
Glycogen Synthase Kinase 3 (GSK3) has conserved functions across species but its role in the kidney is unclear. Here, the authors show that in the kidney podocyte cell of mice and related nephrocyte in Drosophila that GSK3 is a master regulator of function both during development and in maturity.
- J. A. Hurcombe
- , P. Hartley
- & R. J. M. Coward
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| Open AccessMolybdenum-based nanoclusters act as antioxidants and ameliorate acute kidney injury in mice
There are currently no effective therapies available for acute kidney injury (AKI). Here the authors generate molybdenum-based polyoxometalate nanoclusters and show that these have preferential renal uptake and can ameliorate AKI pathology in mice by scavenging reactive oxygen species.
- Dalong Ni
- , Dawei Jiang
- & Weibo Cai
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| Open AccessStructural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption
Cubilin and the transmembrane protein amnionless (AMN) form the endocytic receptor cubam that is essential for intestinal vitamin B12 uptake. Here the authors present the 2.3 Å crystal structure of AMN in complex with the amino-terminal region of cubilin and discuss cubam architecture and disease causing mutations.
- Casper Larsen
- , Anders Etzerodt
- & Christian Brix Folsted Andersen
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| Open AccessMolecular insights into genome-wide association studies of chronic kidney disease-defining traits
The molecular mechanisms that underlie associations in GWAS, incl. chronic kidney disease (CKD), are largely unknown. Here, the authors perform an integrative analysis of genetic, transcriptomic and epigenomic data from human kidney to pinpoint plausible molecular pathways of CKD genetic associations.
- Xiaoguang Xu
- , James M. Eales
- & Maciej Tomaszewski
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| Open AccessCXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury
Injuries in the embryonal kidney can be repaired by a cell migratory response but how this is regulated at a molecular level is unclear. Here, the authors show in mice that deletion of Cxcl12 and Myc delays pronephros injury repair by changing mitochondrial metabolism and glycolysis.
- Toma A. Yakulov
- , Abhijeet P. Todkar
- & Gerd Walz
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| Open AccessHigh-fidelity CRISPR/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis
Suppression of gene expression due to aberrant promoter methylation contributes to organ fibrosis. Here, the authors couple a deactivated Cas9 to the TET3 catalytic domain to induce expression of four antifibrotic genes, and show that lentiviral-mediated delivery is effective in reducing kidney fibrosis in mouse models.
- Xingbo Xu
- , Xiaoying Tan
- & Michael Zeisberg
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| Open AccessHydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels
Mutations in the cation channel PKD2 cause human autosomal dominant polycystic kidney disease but its channel function and gating mechanism are poorly understood. Here authors study PKD2 using electrophysiology and cryo-EM, which identifies hydrophobic gates and proposes a gating mechanism for PKD2.
- Wang Zheng
- , Xiaoyong Yang
- & Xing-Zhen Chen
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| Open AccessEndocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury
The recovery of function upon acute kidney injury is thought to involve tubular cell dedifferentiation and proliferation. Here the authors show that Pax2+ progenitors regenerate tubules via cell division while other tubular cells support function recovery by undergoing hypertrophy through endoreplication.
- Elena Lazzeri
- , Maria Lucia Angelotti
- & Paola Romagnani
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| Open AccessThe CPLANE protein Intu protects kidneys from ischemia-reperfusion injury by targeting STAT1 for degradation
Intu is a planar cell polarity protein known to regulate ciliogenesis during embryonic development. Here, Wang et al. identify a role for Intu in adult kidneys, where they find it promotes degradation of STAT1 and thus prevents cilia loss and cell death upon ischemia-reperfusion injury.
- Shixuan Wang
- , Aimin Liu
- & Zheng Dong
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| Open AccessLkb1 deficiency confers glutamine dependency in polycystic kidney disease
Polycystic kidney disease (PKD) is characterized by the formation of large fluid-filled cysts. Here Flowers and colleagues show that loss of Lkb1, downregulated in PKD, renders kidney cells dependent on glutamine for growth, and suggest that inhibition of glutamine metabolism may prevent cyst development in PKD.
- Ebony M. Flowers
- , Jessica Sudderth
- & Thomas J. Carroll
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| Open AccessImpaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney
Nephropathic cystinosis is a lysosomal storage disease characterized by proximal tubular cell dysfunction. Here Festa and colleagues show that these lysosomal alterations lead to defective autophagic clearance of mitochondria and increased oxidative stress that, in turn, activates the transcription factor ZONAB leading to impaired cell differentiation.
- Beatrice Paola Festa
- , Zhiyong Chen
- & Alessandro Luciani
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| Open AccessORAI channels are critical for receptor-mediated endocytosis of albumin
Patients with diabetic nephropathy suffer from impaired albumin reabsorption by proximal tubular epithelial cells. Here authors use diabetic and transgenic mouse models and in vitro models to show the cause for this lies in the down regulation and internalization of the ion channels, ORAI1-3.
- Bo Zeng
- , Gui-Lan Chen
- & Shang-Zhong Xu
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| Open AccessGenetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis
Crescentic rapidly progressive glomerulonephritis is a severe form of glomerula disease characterized by podocyte proliferation and migration. Here Henique et al. demonstrate that inhibition of miRNA-92a prevents kidney failure by promoting the expression of CDK inhibitor p57Kip2 that regulates podocyte cell cycle.
- Carole Henique
- , Guillaume Bollée
- & Pierre-Louis Tharaux
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| Open AccessMyokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys
Progressive tubule cell damage results in defects in mitochondrial metabolism and exercise seems to be beneficial during chronic kidney disease. Here Peng et al. show that irisin, an exercise-induced myokine, improves kidney energy metabolism by inhibiting TGF-β type 1 receptors and ameliorates fibrosis.
- Hui Peng
- , Qianqian Wang
- & Zhaoyong Hu
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| Open AccessEvidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells
Renal angiomyolipomas (AML) contain a mix of clonal tumour cells. Here, through reverse tumour engineering experiments, mouse genetics and analyses of human AML tumours, the authors provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells.
- Ana Filipa Gonçalves
- , Mojca Adlesic
- & Ian J. Frew
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| Open AccessEpigenome-wide association studies identify DNA methylation associated with kidney function
Genome-wide association studies of kidney function show enrichment of associated genetic variants in regulatory regions. Here, the authors perform epigenome-wide association studies of kidney function and disease, identifying 19 CpG sites significantly associated with these.
- Audrey Y. Chu
- , Adrienne Tin
- & Anna Köttgen
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| Open AccessTargeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis
Mesangial cell-mediated glomerulonephritis is a frequent cause of kidney disease. Here the authors show that celastrol loaded in albumin nanoparticles efficiently targets mesangial cells, and is effective in rat models.
- Ling Guo
- , Shi Luo
- & Zhirong Zhang
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| Open AccessA non-classical view on calcium oxalate precipitation and the role of citrate
The formation mechanism of abundant calcium oxalate biomaterials is unresolved. Here the authors show the early stages of calcium oxalate formation in pure and citrate-bearing solutions by using a titration set-up in conjunction with solution quenching, transmission electron microscopy and analytical ultracentrifugation.
- Encarnación Ruiz-Agudo
- , Alejandro Burgos-Cara
- & Carlos Rodriguez-Navarro
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| Open AccessSirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling
Podocytes are essential components of the renal glomerular filtration barrier and podocyte dysfunction leads to proteinuric kidney disease. Here Liu et al. show that Sirt6 protects podocytes from apoptosis and inflammation by increasing autophagic flux through inhibition of the Notch pathway.
- Min Liu
- , Kaili Liang
- & Fan Yi
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| Open AccessmicroRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism
Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening genetic disease that leads to renal failure. Here Hajarniset al. show that miR-17 modulates cyst progression in ADPKD through metabolic reprogramming of mitochondria and its inhibition slows cyst development and improves renal functions.
- Sachin Hajarnis
- , Ronak Lakhia
- & Vishal Patel
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| Open AccessProtective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
The polyol pathway, which converts glucose into sorbitol and fructose, is active in chronic conditions like hepatic steatosis and chronic kidney disease. Here, Andres-Hernandoet al. show that fructose production promotes renal injury and fructokinase inhibition protects against kidney damage during ischaemic acute kidney disease.
- Ana Andres-Hernando
- , Nanxing Li
- & Miguel A. Lanaspa
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| Open AccessDisposal of iron by a mutant form of lipocalin 2
Iron overload can be either hereditary or acquired via transfusions, and current treatments include the use of iron chelators that have adverse effects in some patients. Here the authors modify siderocalin to enhance iron excretion in urine, and demonstrate therapeutic efficacy in iron overload mouse models.
- Jonathan Barasch
- , Maria Hollmen
- & Andong Qiu
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| Open AccessAn endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy
Nephropathy is a common and hard-to-treat consequence of diabetes. Here Kato et al. show that a megacluster of microRNAs regulates early development of diabetic nephropathy in mice, and that inhibition of the cluster's host long non-coding RNA transcript attenuates disease symptoms, suggesting a new therapy for diabetic nephropathy.
- Mitsuo Kato
- , Mei Wang
- & Rama Natarajan
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| Open AccessThe cell adhesion molecule Fasciclin2 regulates brush border length and organization in Drosophila renal tubules
In Drosophila, Fasciclin 2 (Fas2) has been mainly studied in the nervous system, yet this adhesion protein is more abundant in the adult renal tubule. Here the authors show that Fas2 is essential for brush border maintenance in renal tubules through regulation of microvilli length and organization.
- Kenneth A. Halberg
- , Stephanie M. Rainey
- & Julian A. T. Dow
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| Open AccessGenetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.
- Cristian Pattaro
- , Alexander Teumer
- & Caroline S. Fox
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| Open AccessConcurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells
The growth factors BMP and FGF both stimulate the self-renewal of nephron progenitor cells (NPCs), but how these signals overlap is unclear. Here in the mouse, Muthukrishnan et al. find BMP7 and FGF9 coordinately regulate AP-1 transcriptional activity, promoting G1-S cell cycle progression and NPC proliferation.
- Sree Deepthi Muthukrishnan
- , Xuehui Yang
- & Leif Oxburgh