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Article
| Open Access
Epidermal growth factor receptor activation is essential for kidney fibrosis development
Fibrosis is the progressive accumulation of excess extracellular matrix produced by myofibroblasts leading to organ failure. Here the authors show that expression of the Epidermal Growth Factor Receptor (EGFR) increases in interstitial myofibroblasts in human and mouse fibrotic kidneys, and selective EGFR deletion in the fibroblast/pericyte population inhibits interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins.
- Shirong Cao
- , Yu Pan
- & Raymond C. Harris
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Article
| Open Access
Palmitoyltransferase DHHC9 and acyl protein thioesterase APT1 modulate renal fibrosis through regulating β-catenin palmitoylation
The role and mechanisms for protein palmitoylation in renal fibrosis remain unclear. Here, the authors show that DHHC9 and APT1 catalysed β-catenin S-palmitoylation on Cys300 contributes to renal fibrosis, which may provide a new therapeutic strategy for chronic kidney diseases.
- Mengru Gu
- , Hanlu Jiang
- & Chunsun Dai
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Article
| Open Access
MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
Autosomal dominant tubulointerstitial kidney disease (ADTKD) due to uromodulin mutations is a hereditary kidney disease causing renal fibrosis. Here, the authors show that mesencephalic astrocyte-derived neurotrophic factor can improve defective autophagy/mitophagy and decrease renal scarring in ADTKD.
- Yeawon Kim
- , Chuang Li
- & Ying Maggie Chen
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Article
| Open Access
HCK 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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Article
| Open Access
HDAC9-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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Article
| Open Access
Circular 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 Access
Understanding 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 Access
The 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 Access
Loss 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 Access
Chromatin-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 Access
Loss 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 Access
Fetuin-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 Access
Circulating 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 Access
High-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 Access
Myokine 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
Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence