ArticleJournal of the American Society of Nephrology : JASN2016
Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression.
Article in Journal of the American Society of Nephrology : JASN, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 116 papers, 1 of them a synthesis that pooled it.
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Who cites it
116 citing papers in PubMed, 1 synthesis or guideline pooled it, 196 citations in OpenAlex.
- Extracellular vesicles carrying miRNAs in kidney diseases: a systemic review.Clinical and experimental nephrology · 2020Pooled it
- Post‑translational modifications in diabetic kidney disease (Review).International journal of molecular medicine · 2026Review
- The response to kidney injury is epigenetically regulated through the activation of bivalent genes.American journal of physiology. Renal physiology · 2026Article
- Genetic depletion or pharmacological degradation of EZH2 attenuates renal fibrosis via suppressing Notch signaling.Clinical epigenetics · 2025Article
- Histone methylation of kidney disease: fact or fantasy?Renal failure · 2025Review
- Epigenetic memories induced by hypoxia in AKI-to-CKD transition.Clinical and experimental nephrology · 2025Review
- Histone modification-mediated epigenetic regulation in AKI-to-CKD transition: a cell-type-specific perspective.Journal of translational medicine · 2025Review
- Epigenetic histone modifications in kidney disease and epigenetic memory.Clinical and experimental nephrology · 2025Review
- Machine learning selection of basement membrane-associated genes and development of a predictive model for kidney fibrosis.Scientific reports · 2025Article
- EZH2-mediated macrophage-to-myofibroblast transition contributes to calcium oxalate crystal-induced kidney fibrosis.Communications biology · 2025Article
- UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathway.Scientific reports · 2025Article
- Epigenetic therapeutics attenuate kidney injury and fibrosis by restoring the expression of epigenetically reprogrammed fibrogenic genes and signaling pathways.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2025Article
- Enzymatic post-translational modifications of proteins in chronic kidney disease: mechanisms, regulation, and clinical significance.Frontiers in pharmacology · 2025Review
- Epigenetic Regulation of Ferroptosis in Chronic Kidney Disease: Mechanisms and Implications.Research (Washington, D.C.) · 2025Review
- Identification of key necroptosis-related genes and immune landscape in patients with immunoglobulin A nephropathy.BMC nephrology · 2024Article
- New approaches to acute kidney injury.Clinical kidney journal · 2024Article
- Histone methylation modification and diabetic kidney disease: Potential molecular mechanisms and therapeutic approaches (Review).International journal of molecular medicine · 2024Review
- Sex-specific modulation of renal epigenetic and injury markers in aging kidney.American journal of physiology. Renal physiology · 2024Article
- Epigenetic mechanisms differentially regulate blood pressure and renal dysfunction in male and female Npr1 haplotype mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Role of Histone Modifications in Kidney Fibrosis.Medicina (Kaunas, Lithuania) · 2024Review
56 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issuedErratum.2017
Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Enhancer of zeste homolog 2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. However, the role of EZH2 in renal fibrogenesis remains unexplored. In this study, we found high expression of EZH2 and H3K27me3 in cultured renal fibroblasts and fibrotic kidneys from mice with unilateral ureteral obstruction and humans with CKD. Pharmacologic inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) or GSK126 or siRNA-mediated silencing of EZH2 inhibited serum- and TGFβ1-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of α-smooth muscle actin in the obstructed kidney. Injury to the kidney enhanced Smad7 degradation, Smad3 phosphorylation, and TGFβ receptor 1 expression, and 3-DZNeP administration prevented these effects. 3-DZNeP also suppressed phosphorylation of the renal EGF and PDGFβ receptors and downstream signaling molecules signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 after injury. Moreover, EZH2 inhibition increased the expression of phosphatase and tensin homolog (PTEN), a protein previously associated with dephosphorylation of tyrosine kinase receptors in the injured kidney and serum-stimulated renal interstitial fibroblasts. Finally, blocking PTEN with SF1670 largely diminished the inhibitory effect of 3-DZNeP on renal myofibroblast activation. These results uncovered the important role of EZH2 in mediating the development of renal fibrosis by downregulating expression of Smad7 and PTEN, thus activating profibrotic signaling pathways. Targeted inhibition of EZH2, therefore, could be a novel therapy for treating CKD.
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