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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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Article
| 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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Article
| 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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Article
| 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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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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Article
| 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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Article
| 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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Article
| 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 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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Article
| 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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Article
| 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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Article
| 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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Article
| Open AccessAKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus
Patients suffering from congenital nephrogenic diabetes insipidus (NDI) fail to concentrate urine due to mutations in vasopressin type 2 receptor (V2R). Here Ando et al. show that agents disrupting the interaction between PKA and AKAPs restore aquaporin-2 activity downstream of V2R, offering a therapeutic approach for the treatment of NDI.
- Fumiaki Ando
- , Shuichi Mori
- & Shinichi Uchida
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Article
| 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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Article
| 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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Article
| 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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Article
| Open AccessProstaglandin D2 amplifies lupus disease through basophil accumulation in lymphoid organs
In a lupus environment, basophils accumulate in secondary lymphoid organs where they affect pathogenesis by stimulating autoantibody production. Here the authors show this accumulation is driven by PGD2-induced CXCR4 surface expression and trafficking of basophils.
- Christophe Pellefigues
- , Barbara Dema
- & Nicolas Charles
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Article
| 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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Article
| 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 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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Article
| 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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Article
| 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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Article
| 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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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 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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Article
| 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 AccessProphylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
Acute kidney injury can progress to chronic kidney disease. Here Dehnadiet al. develop a post-ischaemic chronic kidney disease model in cynomolgus monkeys and show that prophylactic inhibition of CD11b/CD18 leukocyte receptor via a monoclonal antibody inhibits progression of kidney disease and fibrosis.
- Abbas Dehnadi
- , A. Benedict Cosimi
- & M. Amin Arnaout
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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 AccessGenetic link between renal birth defects and congenital heart disease
Using forward genetic screen in fetal mice, Gregory Pazour and colleagues describe mutants affecting kidney/urinary tract development. The authors also show that mutants that cause kidney defects overlaps with those leading to congenital heart defects, thus linking renal anomalies and congenital heart disease.
- Jovenal T. San Agustin
- , Nikolai Klena
- & Gregory J. Pazour
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Article
| Open AccessmTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex
Polycystic kidney disease (PKD) is a ciliopathy resulting from defective localization of membrane proteins such as PC-1 to the primary cilium, resulting in renal cysts, and is associated with another cystic genetic disease called tuberous sclerosis complex (TSC). Here the authors use kidney-specific Tsc1 and Pkd1 mice to show that mTORC1 signalling inhibits PC-1 biogenesis as a potential mechanism of TSC/PKD contiguous gene syndrome.
- Monika Pema
- , Luca Drusian
- & Alessandra Boletta
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Article
| Open AccessFAT1 mutations cause a glomerulotubular nephropathy
Steroid-sensitive nephrotic syndrome (SRNS) can cause CKD and necessitate kidney transplant. Here the authors identify FAT1 mutations by homozygosity mapping and whole-exome sequencing in families with SRNS and provide functional mouse and zebrafish evidence that FAT1 is required for normal glomerular and tubular function and that FAT1 mutations can cause SRNS.
- Heon Yung Gee
- , Carolin E. Sadowski
- & Friedhelm Hildebrandt
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Article
| Open AccessCytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis
Kidney stone disease is caused by accumulation of oxalate crystals, which trigger tissue injury, inflammation and cell death. Mulay et al. show that crystals induce cell death in the kidney through necroptosis, and propose that this pathway may be a target for the treatment of crystal-induced disease.
- Shrikant R. Mulay
- , Jyaysi Desai
- & Hans-Joachim Anders
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Article
| Open AccessEndoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2
Proteinuria promotes chronic kidney disease progression. Karoui et al. show that proteinuria stimulates overexpression of iron transporting protein lipocalin-2 via Ca2+release-induced ER stress, which leads to tubular apoptosis, and that inhibition of this pathway by PBA delays renal deterioration in proteinuric mice.
- Khalil El Karoui
- , Amandine Viau
- & Fabiola Terzi
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Article
| Open AccessModelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids
Generating organized kidney tissues from human pluripotent stem cell is a major challenge. Here, Freedman et al. describe a differentiation system forming spheroids and tubular structures, characteristic of these kidney structures, and using CRISPR/Cas9, delete PKD1/2, to model polycystic kidney disease.
- Benjamin S. Freedman
- , Craig R. Brooks
- & Joseph V. Bonventre
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Article
| Open AccessCommon and rare variants associated with kidney stones and biochemical traits
Kidney stone formation is influenced by genetic factors and recurrent stone formation places a significant burden on health care systems. Here Oddsson et al.perform a large-scale genome-wide association study and uncover new genetic variants associated with kidney stone susceptibility and associated biochemical traits.
- Asmundur Oddsson
- , Patrick Sulem
- & Kari Stefansson
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Article
| Open AccessRTN1 mediates progression of kidney disease by inducing ER stress
ER stress is associated with the pathogenesis of chronic kidney disease (CKD) and new CKD therapies are needed. Here the authors show that expression of Rtn1 can control severity of renal disease and that inhibition of its expression can attenuate ER stress and CKD.
- Ying Fan
- , Wenzhen Xiao
- & John C. He
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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
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Article |
Notch2 activation ameliorates nephrosis
The Notch signalling pathway is normally inactive in adult kidneys, but reactivated in kidney diseases. Here the authors show that activation of Notch2 receptors protects renal podocytes from apoptosis, which contrasts with the known detrimental effects of Notch1 signalling on the progression of kidney disease.
- Eriko Tanaka
- , Katsuhiko Asanuma
- & Yasuhiko Tomino
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Article |
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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Article |
Molecular mechanism of the assembly of an acid-sensing receptor ion channel complex
Polycystic kidney disease family proteins form heteromeric complexes with transient receptor potential channel subunits of the TRPP subfamily. Yu and colleagues find that the polycystic kidney disease protein, PKD1L3, is an ion channel pore-forming subunit in the acid-sensing PKD1L3/TRPP3 complex.
- Yong Yu
- , Maximilian H. Ulbrich
- & Jian Yang
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Article
| Open AccessDecreased extra-renal urate excretion is a common cause of hyperuricemia
Hyperuricemia, or gout, is thought to arise either from urate overproduction or from decreased renal excretion of urate. Ichidaet al. show that the extra-renal excretion of urate also has a role in the pathogenesis of hyperuricemia, and propose a new classification for patients with this disease.
- Kimiyoshi Ichida
- , Hirotaka Matsuo
- & Hiroshi Suzuki
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Article
| Open AccessTRPM7 is essential for Mg2+ homeostasis in mammals
Magnesium is an essential element of the diet and is a cofactor for many enzymes. In this study, the channel kinase TRPM7 is shown to be essential for magnesium homeostasis, and heterozygous mice lacking the kinase domain show a defect in absorption of magnesium from the diet.
- Lillia V. Ryazanova
- , Lusliany J. Rondon
- & Alexey G. Ryazanov
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- Acid, base, fluid, electrolyte disorders
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- Fanconi syndrome
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- Obstructive nephropathy
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