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| 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 AccessAnti-VEGFR2 F(ab′)2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy
Poor renal distribution of antibody-based drugs limits the treatment efficiency for diabetic nephropathy and causes side effects. Here, the authors prepare an antibody fragment drug conjugate, antiVEGFR2 F(ab′)2-SS31, improving renal distribution and meriting drug validation in diabetic nephropathy therapy.
- Di Liu
- , Yanling Song
- & Yongzhong Du
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Article
| Open AccessStrong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
African Americans have an elevated risk of developing chronic kidney disease, yet only a fraction of those with high-risk genotypes develop the disease. Here, the authors show that a missense variant in APOL1 has a strong protective effect when co-inherited with the high-risk G2 allele of APOL1, with important implications for clinical practice and translational research.
- Yask Gupta
- , David J. Friedman
- & Simone Sanna-Cherchi
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Article
| Open AccessThe extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome
Although B cell-targeting therapies can provide clinical benefits to children with idiopathic nephrotic syndrome (INS), B lymphocyte subsets have not been extensively studied in this disease. Here, using single-cell RNA sequencing, the authors identify an extrafollicular B cell signature in children with INS.
- Tho-Alfakar Al-Aubodah
- , Lamine Aoudjit
- & Tomoko Takano
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Article
| Open AccessAn integrated organoid omics map extends modeling potential of kidney disease
Lassé et al. show that genes involved in kidney organoid proteomic response to TNFα segregate a subset of individuals with poor outcomes in proteinuric kidney disease, demonstrating the relevance of kidney organoid modeling to human kidney disease.
- Moritz Lassé
- , Jamal El Saghir
- & Markus M. Rinschen
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Article
| Open AccessMulti-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome
Here, the authors have performed a multi-population GWAS meta-analysis of pediatric steroid sensitive nephrotic syndrome cases to discover 12 loci (4 novel), fine-map HLA, implicate kidney and immune factors, and associate the polygenic risk score with earlier disease onset.
- Alexandra Barry
- , Michelle T. McNulty
- & Matthew G. Sampson
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Article
| Open AccessNon-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis
In membranous nephropathy autoantibodies target podocytes of the kidney filter resulting in injury. Here the authors show that the ensuing proteostatic disturbances and proteinuria relate to aberrant interactions of non-functional UCH-L1 enzyme with the proteasome, curtailing its capacity.
- Julia Reichelt
- , Wiebke Sachs
- & Catherine Meyer-Schwesinger
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Article
| Open AccessThe classical pathway triggers pathogenic complement activation in membranous nephropathy
It is generally thought that complement activation in human membranous nephropathy (MN) occurs predominantly via the lectin or alternative pathway. Here, the authors show that the classical pathway is the dominant form of complement activation in MN and a pathogenic driver of the disease.
- Larissa Seifert
- , Gunther Zahner
- & Nicola M. Tomas
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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 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 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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| 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 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 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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Article
| Open AccessSMPDL3b modulates insulin receptor signaling in diabetic kidney disease
Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme known to affect membrane lipid composition. Here, Mitrofanova et al. show that increased expression of SMPDL3b in diabetes impairs insulin signaling and ceramide-1-phosphate (C1P) availability in podocytes, and that C1P supplementation protects mice from diabetic kidney disease.
- A. Mitrofanova
- , S. K. Mallela
- & A. Fornoni
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Article
| 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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Article
| 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 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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Article
| 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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Article
| 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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Article
| Open AccessmiR-93 regulates Msk2-mediated chromatin remodelling in diabetic nephropathy
Podocyte injury is central to kidney dysfunction in diabetic nephropathy. Here the authors show that Msk2 is a target of miR-93 and this interaction mediates pathogenic chromatin remodelling in diabetic nephropathy.
- Shawn S. Badal
- , Yin Wang
- & Farhad R. Danesh
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Article
| Open AccessIdentification of new susceptibility loci for IgA nephropathy in Han Chinese
IgA nephropathy is a major cause of end-stage renal disease in China, occurring at a high frequency in Asian populations. Here Li and colleagues conduct a four-stage genome-wide association study in a Chinese population, identifying novel loci and variants associated with disease risk.
- Ming Li
- , Jia-Nee Foo
- & Jian-Jun Liu
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Article
| Open AccessDefective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy
Diabetic kidney disease is associated with ER stress in podocytes. Here the authors use various genetically modified mouse models to study ER-stress-related signalling pathways and propose a mechanistic framework that links insulin signalling with ER stress in podocytes of diabetic mice.
- Thati Madhusudhan
- , Hongjie Wang
- & Berend Isermann