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| Open AccessThe chromatin landscape of healthy and injured cell types in the human kidney
Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.
- Debora L. Gisch
- , Michelle Brennan
- & Michael T. Eadon
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| Open AccessPolygenic risk alters the penetrance of monogenic kidney disease
Polygenic factors may partially explain the observed variability in the penetrance of monogenic diseases. Here, the authors show that a polygenic risk score for chronic kidney disease is significantly associated with a higher risk of renal dysfunction in the two most common monogenic forms of kidney disease, suggesting that accounting for polygenic factors improves risk stratification in monogenic kidney disease.
- Atlas Khan
- , Ning Shang
- & Krzysztof Kiryluk
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| Open AccessChoroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment
In patients with CKD, there is an unmet need for biomarkers that reliably track kidney injury. Here, in a series of prospective studies, the authors show that retinal OCT metrics reflect kidney injury, are modified by treatments for kidney disease and can predict future decline of kidney function.
- Tariq E. Farrah
- , Dan Pugh
- & Neeraj Dhaun
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| Open AccessMicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease
Cisplatin, a chemotherapy drug, can cause long-lasting kidney injury. The authors explore miRNA:mRNA interactions in cisplatin-injured kidneys and find that such a cisplatin inducible miRNA as miR-429-3p suppresses the catabolism of branched-chain amino acids, leading to stimulation of ferroptotic cell death.
- Hisakatsu Sone
- , Tae Jin Lee
- & Sang-Ho Kwon
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| Open AccessLongitudinal tracking of acute kidney injury reveals injury propagation along the nephron
The mechanisms of failed tubule repair after acute kidney injury are incompletely understood. Here, the authors show spatial and temporal analysis of cycling cells relative to initial necrosis and postulate pronounced injury expansion into non-necrotic tissue regions, predictive of tubule atrophy.
- Luca Bordoni
- , Anders M. Kristensen
- & Ina Maria Schiessl
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| Open AccessHCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy
The authors previously reported HCK was associated with kidney inflammation and fibrosis. Here, they further unravel a mechanism of HCK regulating autophagy within macrophages, altering their polarization, proliferation, and migration and they also developed a more selective HCK inhibitor.
- Man Chen
- , Madhav C. Menon
- & Chengguo Wei
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| Open AccessIntrinsic TGF-β signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease
Chronic kidney disease (CKD) is a disease that irreversibly leads to loss of renal function. Here, the authors demonstrate the beneficial effect of intrinsic TGF-b signaling on mitochondrial function and inflammation in the proximal tubule epithelium in response to kidney injury.
- Merve Kayhan
- , Judith Vouillamoz
- & Stellor Nlandu Khodo
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| Open AccessHDAC9-mediated epithelial cell cycle arrest in G2/M contributes to kidney fibrosis in male mice
Although accumulating evidence indicates that epithelial cell cycle G2/M arrest is involved in kidney fibrosis, the underlying mechanism remains unclear. Here, the authors show that HDAC9 is upregulated in the fibrotic kidney and promotes epithelial cell cycle arrest in G2/M by regulating STAT1.
- Yang Zhang
- , Yujie Yang
- & Fan Yi
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| Open AccessDNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives chronic kidney disease progression in male mice
Kidney injury leads to fibrosis during the progression of chronic kidney disease. Here the authors report that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives chronic kidney disease progression in a study with male mice, potentially via TAF7/RAPTOR/mTORC1 signaling.
- Yunwen Yang
- , Suwen Liu
- & Aihua Zhang
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| Open AccessImputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank
An exome wide association study of UK Biobank data revealed 158 variants and 105 genes significantly associated with kidney function traits and disease. The findings are supported by functional evidence for a previously unreported mutation in CLDN10.
- Matthias Wuttke
- , Eva König
- & Christian Fuchsberger
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| Open AccessLong-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice
Huang et al. investigated the effects of long-term statins administration in a mouse model for diabetes and found that it can worsen insulin resistance, renal inflammation and fibrosis. Statins increased renal lipid uptake and inhibited fatty acid oxidation, contributing to diabetic nephropathy.
- Tong-sheng Huang
- , Teng Wu
- & Wei-bin Cai
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| Open AccessEpigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease
Approximately 40 percent of people with type 1 diabetes develop kidney disease, but the risk factors are not well understood. Here, the authors identify DNA methylation signatures associated with diabetic kidney disease, of which 21 biomarkers predict the development of kidney failure.
- Laura J. Smyth
- , Emma H. Dahlström
- & Amy Jayne McKnight
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| Open AccessTargeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease
Repair processes in kidney are impaired in severe disease. Here, the authors show that in kidney failure, genetic or pharmacologic inhibition of IL11 releases the brake on regeneration, reverses tissue damage and restores kidney function.
- Anissa A. Widjaja
- , Sivakumar Viswanathan
- & Stuart A. Cook
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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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 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 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 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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| 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 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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| 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 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 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 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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| 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