Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development
Hyun Mi Kang,Seon Ho Ahn,Peter S. Choi,Yi-An Ko,Seung Hyeok Han,Frank Chinga,Ae Seo Deok Park,Jianling Tao,Kumar Sharma,James Pullman,Erwin P. Bottinger,Ira J. Goldberg,Katalin Susztak +12 more
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TLDR
It is found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls, raising the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.Abstract:
Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.read more
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Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease
Jihwan Park,Rojesh Shrestha,Chengxiang Qiu,Ayano Kondo,Shizheng Huang,Max Werth,Mingyao Li,Jonathan Barasch,Katalin Susztak +8 more
TL;DR: It is inferred that inherited kidney diseases that arise from distinct genetic mutations but share the same phenotypic manifestation originate from the same differentiated cell type, and that the collecting duct in kidneys of adult mice generates a spectrum of cell types through a newly identified transitional cell.
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Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis
Sara Lovisa,Valerie S. LeBleu,Björn Tampe,Hikaru Sugimoto,Komal Vadnagara,Julienne L. Carstens,Chia Chin Wu,Yohannes Hagos,Birgitta C. Burckhardt,Tsvetelina Pentcheva-Hoang,Hersharan Nischal,James P. Allison,Michael Zeisberg,Raghu Kalluri +13 more
TL;DR: In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis.
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Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk
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Fibrosis: from mechanisms to medicines
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Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression
TL;DR: Experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression.
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TL;DR: Remodelling cellular metabolism constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
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BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury
Michael Zeisberg,Jun-ichi Hanai,Hikaru Sugimoto,Tadanori Mammoto,David M. Charytan,Frank Strutz,Raghu Kalluri +6 more
TL;DR: It is reported that BMP-7 reverses TGF-β1–induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule, which provides evidence of cross talk between B MP-7 and TGF -β1 in the regulation of EMT in health and disease.
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Fate Tracing Reveals the Pericyte and Not Epithelial Origin of Myofibroblasts in Kidney Fibrosis
Benjamin D. Humphreys,Benjamin D. Humphreys,Shuei-Liong Lin,Shuei-Liong Lin,Akio Kobayashi,Thomas E. Hudson,Brian T. Nowlin,Joseph V. Bonventre,Joseph V. Bonventre,M. Todd Valerius,Andrew P. McMahon,Jeremy S. Duffield,Jeremy S. Duffield +12 more
TL;DR: Data indicate that therapeutic strategies directly targeting pericyte differentiation in vivo may productively impact fibrotic kidney disease.
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Mouse Models of Diabetic Nephropathy
Frank C. Brosius,Charles E. Alpers,Erwin P. Bottinger,Matthew D. Breyer,Thomas M. Coffman,Susan B. Gurley,Raymond C. Harris,Masao Kakoki,Matthias Kretzler,Edward H. Leiter,Moshe Levi,Richard A. McIndoe,Kumar Sharma,Oliver Smithies,Katalin Susztak,Nobuyuki Takahashi,Takamune Takahashi +16 more
TL;DR: This interim report and an online supplement detail the progress made toward a complete murine model of human diabetic kidney disease and the critical analysis of existing murine models, which substantially enhances the understanding of this disease process.
Journal ArticleDOI
TGF-β signaling in renal disease
Erwin P. Bottinger,Markus Bitzer +1 more
TL;DR: Evidence is described in support of nonlinear models and functional roles of TGF-s signaling in mediating apoptosis and epithelial-to-mesenchymal transdifferentiation (EMT) in chronic progressive renal disease.
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