A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction
Journal
EMBO Molecular Medicine
Journal Volume
11
Journal Issue
5
Pages
e9828
Date Issued
2019
Author(s)
Abstract
Diabetic nephropathy is the leading cause of end-stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up-regulation of its downstream target KLF10. Overexpression of KLF10 in podocytes not only represses multiple podocyte-specific markers including nephrin, but also conversely increases KDM6A expression. We further show that KLF10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM6A or KLF10 in mice significantly suppresses diabetes-induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM6A and KLF10 proteins or mRNAs are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM6A–KLF10 feedback loop may be beneficial to attenuate diabetes-induced kidney injury. ? 2019 The Authors. Published under the terms of the CC BY 4.0 license
Subjects
diabetic nephropathy; epigenetics; KDM6A; KLF10; podocyte dysfunction
SDGs
Other Subjects
DNA (cytosine 5) methyltransferase 1; histone demethylase; KDM6A protein; KLF10 protein; kruppel like factor; messenger RNA; nephrin; unclassified drug; early growth response factor; histone demethylase; KDM6A protein, human; KLF10 protein, human; KLF10 protein, mouse; kruppel like factor; membrane protein; nephrin; protein binding; Utx protein, mouse; Article; diabetic nephropathy; down regulation; enzyme inactivation; epigenetics; feedback system; human; podocyte; positive feedback; priority journal; protein expression; protein protein interaction; proteinuria; upregulation; animal; C57BL mouse; exosome; genetic epigenesis; genetics; kidney; knockout mouse; male; metabolism; nucleotide sequence; pathology; pathophysiology; phenotype; physiological feedback; podocyte; promoter region; transformed cell line; urine; Animals; Base Sequence; Cell Line, Transformed; Diabetic Nephropathies; Down-Regulation; Early Growth Response Transcription Factors; Epigenesis, Genetic; Exosomes; Feedback, Physiological; Histone Demethylases; Humans; Kidney; Kruppel-Like Transcription Factors; Male; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Podocytes; Promoter Regions, Genetic; Protein Binding
Publisher
Blackwell Publishing Ltd
Type
journal article