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| Open AccessChromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
Renal tubular epithelial cells (TECs) can initiate an adaptive or maladaptive response after injuries of different severity. Here, the authors elucidate a chromatin-mediated mechanism underlying the responses of TECs to varying kidney injuries.
- Xinyi Cao
- , Jiuchen Wang
- & Lirong Zhang
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Article
| Open AccessGenetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
Immunoglobulin A protects against infectious disease and contributes to autoimmune and inflammatory disorders. Here, the authors perform a genome-wide association study for serum IgA levels, identifying 20 genome-wide significant loci, providing new insights into the genetic regulation of IgA levels.
- Lili Liu
- , Atlas Khan
- & Krzysztof Kiryluk
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Article
| Open AccessCircular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair
G2/M arrest of epithelial cells leads to fibrosis with unclear mechanisms. This study identifies a protein-encoding circRNA, circBNC2, which inhibits epithelial cells G2/M arrest to prevent fibrotic maladaptive repair in damaged kidney and liver, revealing a potential intervention target for fibrosis.
- Peng Wang
- , Zhitao Huang
- & Fan Fan Hou
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Article
| Open AccessUnderstanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context
Renal fibrosis is a progressive process with complex etiopathology, causing organ failure. Here authors present a mathematical model, based on an in vitro system faithfully contemplating macrophage-fibroblast interaction and the metabolic-immunologic signals that are affecting kidney fibrosis, that is applicable to kidney transplant failure.
- Elisa Setten
- , Alessandra Castagna
- & Massimo Locati
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Article
| Open AccessDefining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis
Autosomal dominant polycystic kidney disease (ADPKD) is a complicated disease that involves numerous cell types. Here the authors used a multiomics approach consisting of single nucleus transcriptomes and epigenomes to redefine cell states in ADPKD and to dissect the cellular interactions and molecular mechanisms of ADPKD.
- Yoshiharu Muto
- , Eryn E. Dixon
- & Benjamin D. Humphreys
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Article
| Open AccessThe gut microbe Bacteroides fragilis ameliorates renal fibrosis in mice
Renal fibrosis is the main pathological feature of chronic kidney disease (CKD). Here, the authors show that live B. fragilis can attenuate renal fibrosis via the upregulation of SGLT2, which contributes to renal reabsorption of 1,5-AG, and that 1,5-AG improves renal fibrosis via inhibition of oxidative stress and inflammation.
- Wei Zhou
- , Wen-hui Wu
- & Zhi-hao Zhang
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Article
| Open AccessMultimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression
Diabetic kidney disease leads to changes in glucose metabolism and inflammation. Here the authors use multimodal single cell sequencing to show that this disease leads to reduced accessibility of glucocorticoid receptor binding sites in the proximal tubule and increased gluconeogenesis.
- Parker C. Wilson
- , Yoshiharu Muto
- & Benjamin D. Humphreys
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Article
| Open AccessReversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression
Persistent diabetic complications despite controlled blood glucose levels, known as hyperglycemic memory, remain a poorly understood phenomenon in diabetic kidney disease. Here the authors identify senescence-associated gene p21 as a regulator of hyperglycemic memory, the suppression of which improves hyperglycemic memory and renal function.
- Moh’d Mohanad Al-Dabet
- , Khurrum Shahzad
- & Berend Isermann
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Article
| Open AccessMidkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment
The tumour microenvironment in mTORC1 hyperactive cancers remains poorly characterised. Here, integrative analysis in tuberous sclerosis complex tumours with mTORC1 hyperactivity suggests distinct cell states associated with rapamycin resistance and immune modulation.
- Yan Tang
- , David J. Kwiatkowski
- & Elizabeth P. Henske
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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 AccessPKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression
ADPKD, a common aetiology of kidney failure, is caused by heterozygous PKD1 or PKD2 mutations. Here the authors show that preventing 3′-UTR cis-inhibition of mRNAs produced by the non-inactivated PKD1/2 alleles ameliorates preclinical ADPKD.
- Ronak Lakhia
- , Harini Ramalingam
- & Vishal Patel
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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 AccessA Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling
Klotho is an anti-ageing protein whose expression is downregulated in chronic kidney disease, but the large size of the protein makes it challenging to deliver therapeutically. Here, the authors develop a Klotho-derived peptide, and show that it recapitulates the anti-fibrotic action of Klotho and prevents kidney fibrosis in mice by targeting TGF-β signalling.
- Qian Yuan
- , Qian Ren
- & Youhua Liu
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Article
| Open AccessMeta-analyses identify DNA methylation associated with kidney function and damage
Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.
- Pascal Schlosser
- , Adrienne Tin
- & Alexander Teumer
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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 AccessChromatin-accessibility estimation from single-cell ATAC-seq data with scOpen
scATAC-Seq yields data that is extremely sparse. Here, the authors present a computationally efficient imputation method called scOpen that improves the downstream analyses of scATAC-Seq data and use it to identify transcriptional regulators of kidney fibrosis.
- Zhijian Li
- , Christoph Kuppe
- & Ivan G. Costa
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Article
| Open AccessA single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
Identifying causal variants and genes is an essential step in interpreting GWAS loci. Here, the authors investigate a kidney disease GWAS locus with functional genomics data, CRISPR editing and mouse experiments to identify DPEP1 and CHMP1A as putative kidney disease genes via ferroptosis.
- Yuting Guan
- , Xiujie Liang
- & Katalin Susztak
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Article
| Open AccessDeep learning-based transformation of H&E stained tissues into special stains
Performing multiple histological stains on a biopsy can be costly and time consuming. Here the authors present a method for the digital transformation of H&E stained tissue into special stains (e.g., PAS, Masson’s Trichrome and Jones silver stain), and demonstrate that it improves diagnoses over the use of H&E only.
- Kevin de Haan
- , Yijie Zhang
- & Aydogan Ozcan
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Article
| Open AccessThe enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals
Inositol hexakisphosphate kinase (IP6K) is involved in diverse cellular signalling pathways, but the physiological roles of IP6K in vivo remain unknown in mammals. Here, the authors show that the enzymatic activity of IP6K is essential for phosphate regulation in vivo.
- Yusuke Moritoh
- , Shin-ichi Abe
- & Masanori Watanabe
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Article
| Open AccessCompounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease
This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.
- Matthew B. Wright
- , Javier Varona Santos
- & Alessia Fornoni
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Article
| Open AccessExtracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease is characterized by the formation of cysts in the kidney. Here the authors show that cystic extracellular vesicles/exosomes play a critical role in regulating the biology and function of adjacent cells, including renal epithelial cells, fibroblasts and macrophages, and contribute to renal cyst growth.
- Hao Ding
- , Linda Xiaoyan Li
- & Xiaogang Li
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Article
| Open AccessDiscovery and prioritization of variants and genes for kidney function in >1.2 million individuals
Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.
- Kira J. Stanzick
- , Yong Li
- & Thomas W. Winkler
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Article
| Open AccessHuman kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to acute kidney injury. The authors describe that SARS-COV-2 can directly infect human kidney, possibly mediating tubular pathogenesis.
- Bo Diao
- , Chenhui Wang
- & Yongwen Chen
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Article
| Open AccessLoss of endothelial glucocorticoid receptor accelerates diabetic nephropathy
The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.
- Swayam Prakash Srivastava
- , Han Zhou
- & Julie Goodwin
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Article
| Open AccessCatalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics
Reactive oxygen species management is a practical strategy that can reduce the risk of chemotherapy-induced acute kidney injury, but at the cost of chemotherapeutic efficacy. Here the authors report catalytic activity tunable ceria nanoparticles as context-dependent reactive oxygen species scavengers, which can prevent chemotherapy-induced acute kidney injury without interfering with chemotherapeutic agents.
- Qinjie Weng
- , Heng Sun
- & Daishun Ling
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Article
| Open AccessFetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress
Intrauterine growth restriction is associated with increased risk for chronic diseases in adults. Here the authors identify fetuin-A as a HIF target gene and describe its protective role in the kidney, counteracting disease mechanisms such as calcification, macrophage polarization, and fibrosis.
- Stefan Rudloff
- , Mathilde Janot
- & Uyen Huynh-Do
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Article
| Open AccessA DNA origami-based aptamer nanoarray for potent and reversible anticoagulation in hemodialysis
Safe haemodialysis is essential for patients with acute kidney injury and renal failure. Here the authors present a DNA origami-based approach with high affinity and specificity to thrombin, inhibiting coagulation.
- Shuai Zhao
- , Run Tian
- & Baoquan Ding
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Article
| Open AccessCross-site transportability of an explainable artificial intelligence model for acute kidney injury prediction
Artificial intelligence (AI) has demonstrated promise in predicting acutekidney injury (AKI), however, clinical adoption of these models requires interpretability and transportability across sites. Here, the authors develop an AKI prediction model and a measure for model transportability across six independent health systems.
- Xing Song
- , Alan S. L. Yu
- & Mei Liu
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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 AccessIRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4
The pathogenic mechanisms of cardiorenal syndrome type 4 (CRS4) remain unclear. Here, the authors identify IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling as a contributor to CRS4 pathogenesis, thus providing potential new targets for reducing cardiovascular events in CKD patients.
- Yinghui Huang
- , Shaobo Wang
- & Jinghong Zhao
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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 AccessExplainable artificial intelligence model to predict acute critical illness from electronic health records
Acute critical illness is often preceded by deterioration of routinely measured clinical parameters, e.g., blood pressure and heart rate. Here, the authors develop an explainable artificial intelligence early warning score system for its early detection.
- Simon Meyer Lauritsen
- , Mads Kristensen
- & Bo Thiesson
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Article
| Open AccessEnhancer and super-enhancer dynamics in repair after ischemic acute kidney injury
Acute kidney injury is a major health problem amongst hospitalized patients. Here the authors provide a comprehensive characterization of enhancer and super-enhancer elements, and the transcription factor motifs associated with these elements in response to kidney injury in vivo; providing insight into the regulation of kidney repair.
- Julia Wilflingseder
- , Michaela Willi
- & Joseph V. Bonventre
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Article
| Open AccessUltrasmall copper-based nanoparticles for reactive oxygen species scavenging and alleviation of inflammation related diseases
Oxidative stress is involved in several diseases and is a target for intervention. Here, the authors report on the synthesis of ultrasmall copper-based nanozymes as reactive oxygen species scavengers and demonstrate improved treatment outcomes in acute liver and kidney injury and wound healing in vivo.
- Tengfei Liu
- , Bowen Xiao
- & Jun Deng
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Article
| Open AccessDevelopment of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5
Alport syndrome is a progressive inherited nephritis accompanied by sensorineural loss of hearing and ocular abnormalities, for which there is currently no effective therapy. Here, the authors develop an exon-skipping therapy using an antisense-oligonucleotide and show it is effective in mouse models.
- Tomohiko Yamamura
- , Tomoko Horinouchi
- & Kandai Nozu
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Article
| Open AccessComprehensive aptamer-based screening identifies a spectrum of urinary biomarkers of lupus nephritis across ethnicities
Developing noninvasive diagnostic biomarkers for lupus nephritis (LN) diagnosis is an important clinical goal. Here the authors identify urinary proteins correlated with active LN and disease severity, which differ across ethnicities but collectively outperform the current clinical method.
- Samantha Stanley
- , Kamala Vanarsa
- & Chandra Mohan
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Article
| Open AccessA kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury
Protein kinases have emerged as critical regulators of disease pathogenesis. Here, the authors have utilized kinome-wide screening approaches to reveal a pathogenic role of CDKL5 kinase in acute kidney injury, which is dependent on suppression of a SOX9-associated transcriptional network.
- Ji Young Kim
- , Yuntao Bai
- & Navjot Singh Pabla
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Article
| Open AccessThe genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.
- Jingyuan Xie
- , Lili Liu
- & Krzysztof Kiryluk
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Article
| Open AccessImpaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
Methylmalonic acidemia is an inherited metabolic disease caused by loss or mutation of the enzyme MMUT. Here the authors use cell and animal models to show that MMUT mutations lead to defective mitophagy and stress in kidney cells, contributing to the pathogenesis in methylmalonic acidemia patients.
- Alessandro Luciani
- , Anke Schumann
- & Olivier Devuyst
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Article
| Open AccessGut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection
Urinary tract infections (UTIs) are associated with changes in the gut microbiome. Here, the authors evaluate the relationship between the gut microbiome and development of UTI in kidney transplant patients and show that uropathogenic gut abundance might represent a risk factor for development of bacteriuria and UTI.
- Matthew Magruder
- , Adam N. Sholi
- & John Richard Lee
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Article
| Open AccessGenetic variants of calcium and vitamin D metabolism in kidney stone disease
Kidney stones form in the presence of overabundance of crystal-forming substances such as Ca2+ and oxalate. Here, the authors report genome-wide association analyses for kidney stone disease, report seven previously unknown loci and find that some of these loci also associate with Ca2+ concentration and excretion.
- Sarah A. Howles
- , Akira Wiberg
- & Dominic Furniss
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Article
| Open AccessArctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes
Arctigenin (ATG) is the major active component of a Chinese herbal remedy known to reduce proteinuria in patients with diabetic kidney disease (DKD). Here, Zhong et al. identify PP2A as a pharmacological target of ATG in podocytes, and find that PP2A is responsible for some of the beneficial effects of ATG in mouse models of DKD.
- Yifei Zhong
- , Kyung Lee
- & Ruijie Liu
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Article
| Open AccessDiscovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD.
- Edmund C. Lee
- , Tania Valencia
- & Vishal Patel
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Article
| Open AccessGenome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.
- Alexander Teumer
- , Yong Li
- & Anna Köttgen
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Article
| Open AccessMapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program
Persistently low levels of estimated glomerular filtration rate (eGFR) are a biomarker of chronic kidney disease. Here, the authors reinterpret the genetic architecture of kidney function across ancestries, to identify not only genes, but the tissue and anatomical contexts of renal homeostasis.
- Jacklyn N. Hellwege
- , Digna R. Velez Edwards
- & Adriana M. Hung
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Article
| 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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Article
| 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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- Acid, base, fluid, electrolyte disorders
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- Obstructive nephropathy
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- Phosphorus metabolism disorders
- Polycystic kidney disease
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