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| 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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| Open AccessGWAS for urinary sodium and potassium excretion highlights pathways shared with cardiovascular traits
Levels of sodium and potassium in urine are associated with cardiovascular traits. Here, Pazoki et al. perform genome-wide association studies for urinary sodium and potassium secretion and identify 50 and 13 novel loci, respectively, some of which show a potential causal relationship with blood pressure based on MR analysis.
- Raha Pazoki
- , Evangelos Evangelou
- & Abbas Dehghan
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| Open AccessA glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier
The glomerular filtration barrier is a complex structure in charge of renal ultrafiltration. Here the authors present a glomerulus-on-a-chip for disease modelling and high-throughput drug screening where human podocytes and human glomerular endothelial cells are separated by an extracellular matrix resembling the in vivo basement membrane.
- Astgik Petrosyan
- , Paolo Cravedi
- & Stefano Da Sacco
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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 AccessA 3,2-Hydroxypyridinone-based Decorporation Agent that Removes Uranium from Bones In Vivo
In vivo decorporation of U(VI) from bones is an unsolved challenge because of the formation of stable uranium phosphate complexes. Here, the authors develop a hydroxypyridonone-based ligand with strong uranium complexation and low cytotoxicity. They find this ligand effectively removes uranium from kidney and bones in mice, and is suitable for oral administration.
- Xiaomei Wang
- , Xing Dai
- & Shuao Wang
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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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| 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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Article
| Open AccessGeneration of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats
The use of pluripotent-stem cell derived organs for transplantation would be promising, if organs can be grown in a suitable host. Here, the authors use interspecific blastocyst complementation to generate a mouse pluripotent stem cell-derived kidney in anephric Sall1 mutant rats.
- Teppei Goto
- , Hiromasa Hara
- & Masumi Hirabayashi
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Article
| Open AccessLin28 and let-7 regulate the timing of cessation of murine nephrogenesis
Nephrogenesis ceases after postnatal day 2 in the mouse or after the 36th week of gestation in humans, but how this is regulated is unclear. Here, the authors identify a role for the RNA-binding protein Lin28 and suppression of let-7 microRNA in regulating the duration of nephrogenesis.
- Alena V. Yermalovich
- , Jihan K. Osborne
- & George Q. Daley
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| Open AccessTrans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
Estimated glomerular filtration rate (eGFR) is a measure of kidney function used to define chronic kidney disease. Here, Morris et al. perform trans-ethnic genome-wide meta-analyses for eGFR in 312,468 individuals and identify novel loci and downstream putative causal genes.
- Andrew P. Morris
- , Thu H. Le
- & Nora Franceschini
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Article
| 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 AccessLarge-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels
Elevated serum urate levels are a risk factor for gout. Here, Tin et al. perform whole-exome sequencing in 19,517 individuals and detect low-frequency genetic variants in urate transporter genes, SLC22A12 and SLC2A9, associated with serum urate levels and confirm their damaging nature in vitro and in silico.
- Adrienne Tin
- , Yong Li
- & Anna Köttgen
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Article
| 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 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 AccessGeneration of interspecies limited chimeric nephrons using a conditional nephron progenitor cell replacement system
The transplantation of tissue-specific progenitor cells may be an approach in organ regeneration. Here the authors show that the nephron progenitor population of a developing mouse kidney, when ablated, can be replaced by exogenously supplied rat nephron progenitors, generating interspecies nephrons.
- S. Yamanaka
- , S. Tajiri
- & T. Yokoo
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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 AccessHuman mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function
Mesenchymal stromal cells drive renal regeneration following injury. Here, the authors show that human mesenchymal stromal cells, when transplanted into mice with acute kidney injury, stimulate renal tubular cell growth and enhance mitochondrial function via SIRT3.
- Luca Perico
- , Marina Morigi
- & Ariela Benigni
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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 AccessHyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus
Nrf2 regulates oxidative and electrophilic stress responses by modulating the expression of enzymes involved in detoxification pathways. Here Suzukiet al. show that Nrf2 activation in early tubular development promotes nephrogenic diabetes insipidus by regulating aquaporin 2 expression and trafficking and water permeability.
- Takafumi Suzuki
- , Shiori Seki
- & Masayuki Yamamoto
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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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Article
| Open AccessCD8+ T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension
T cells contribute to development of high blood pressure but their role in salt-sensitive hypertension is less clear. Liuet al. show that CD8+ T cells upregulate and activate Na-Cl co-transporter NCC in distal convoluted tubules via direct cell-cell contact and ROS-Src activation, leading to Na+retention and salt-sensitive hypertension.
- Yunmeng Liu
- , Tonya M. Rafferty
- & Shengyu Mu
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Article
| Open AccessWnt5a induces renal AQP2 expression by activating calcineurin signalling pathway
The water channel AQP2 mediates the concentration of urine in the kidney. Here Ando et al. show that Wnt5 promotes collecting duct permeability by regulating AQP2 expression and localization through activation of the calmodulin/calcineurin signalling pathway.
- Fumiaki Ando
- , Eisei Sohara
- & Shinichi Uchida
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Article
| 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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Article
| Open AccessA critical role for NF2 and the Hippo pathway in branching morphogenesis
Branching morphogenesis is essential for the formation of most epithelial organs. Here, the authors show that Neurofibromatosis 2 (NF2), the Hippo pathway kinases LATS1 and LATS2, and the transcriptional co-activators YAP and TAZ control tip identity, RET signalling and branching morphogenesis in the mouse kidney.
- Antoine Reginensi
- , Leonie Enderle
- & Helen McNeill
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| 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
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WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors
The transcription factor Wilms’ tumour 1 (WT1) regulates kidney development, and Wt1 mutations are associated with renal cancer. Here the authors identify WT1 target genes in renal progenitors during early kidney development in mouse embryos and show that loss of Wt1suppresses FGF and induces BMP signalling.
- Fariba Jian Motamedi
- , Danielle A. Badro
- & Andreas Schedl
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Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis
Loss-of-function mutations in PKD1, the gene encoding the plasma membrane receptor Polycystin-1, lead to renal cyst formation in polycystic kidney disease. Here, Castelli et al. show that Polycystin-1 interacts with the Par3 polarity complex and has a role in the morphogenesis of kidney tubules during mouse development.
- Maddalena Castelli
- , Manila Boca
- & Alessandra Boletta
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The phosphatase Dullard negatively regulates BMP signalling and is essential for nephron maintenance after birth
Kidney maintenance and function are essential for a healthy organism. Here Nishinakamura and colleagues show that the phosphatase Dullard suppresses BMP signalling and apoptosis in the mouse kidney and that Dullard is required for the maintenance of functional nephrons after birth.
- Masaji Sakaguchi
- , Sazia Sharmin
- & Ryuichi Nishinakamura
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ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney
Cells must be able to sense and respond to changes in osmotic pressure, which can be lethal. Here, Naguro and colleagues reveal a role for the protein kinase ASK3 in sensing osmotic stress in the mouse kidney and show that ASK3 contributes to the regulation of blood pressure.
- Isao Naguro
- , Tsuyoshi Umeda
- & Hidenori Ichijo
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| Open AccessOuabain protects against adverse developmental programming of the kidney
Poor maternal nutrition is known to affect fetal kidney development. This study shows that the sodium potassium ATPase ligand, ouabain, protects kidneys from cell death induced by serum starvationin vitro and from abnormal kidney development due to a low-protein diet in vivo.
- Juan Li
- , Georgiy R. Khodus
- & Anita Aperia