ArticleKidney international2012
Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation.
Article in Kidney international, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 62 citations in OpenAlex.
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- Histone deacetylases and their inhibitors in kidney diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
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- Therapeutic advances in ADPKD: the future awaits.Journal of nephrology · 2022Review
- Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.Frontiers in molecular biosciences · 2022Review
- Chromatin Methylation Abnormalities in Autosomal Dominant Polycystic Kidney Disease.Frontiers in medicine · 2022Review
- Recent Discoveries in Epigenetic Modifications of Polycystic Kidney Disease.International journal of molecular sciences · 2021Review
- Epithelial proliferation and cell cycle dysregulation in kidney injury and disease.Kidney international · 2021Review
- Epigenetics and cell cycle regulation in cystogenesis.Cellular signalling · 2020Review
- A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2Scientific reports · 2020Article
- Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions.Journal of cellular physiology · 2019Review
- Cux1 regulation of the cyclin kinase inhibitor p27Gene: X · 2019Article
- Histone Deacetylase Inhibitors Reduce Cysts by Activating Autophagy in Polycystic Kidney Disease.Kidney diseases (Basel, Switzerland) · 2019Article
- Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease.The American journal of pathology · 2018Article
- Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells.Cell death & disease · 2018Article
- Profiling of miRNAs and target genes related to cystogenesis in ADPKD mouse models.Scientific reports · 2017Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The pan-histone deacetylase (HDAC) inhibitor, trichostatin A, was found to reduce cyst progression and slow the decline of kidney function in Pkd2 knockout mice, model of autosomal dominant polycystic kidney disease (ADPKD). Here we determine whether HDAC inhibition acts by regulating cell proliferation to prevent cyst formation, or by other mechanisms. The loss of Pkd1 caused an upregulation of the inhibitor of differentiation 2 (Id2), a transcription regulator, triggering an Id2-mediated downregulation of p21 in mutant mouse embryonic kidney cells in vitro. Using mouse embryonic kidney cells, mutant for Pkd1, we found that trichostatin A decreased Id2, which resulted in upregulation of p21. Further, phosphorylated retinoblastoma (Rb), usually regulated by Cdk2/Cdk4 activity, was also reduced in these cells. Since these latter enzymes are under the control of p21, these studies suggest that the proliferation of cyst epithelial cells that is reduced by trichostatin A might result from p21 upregulation, or alternatively through the Rb-E2F pathway. Additional studies showed that Id2 directly bound to Rb, releasing the transcription activator E2F from transcriptionally inactive Rb-E2F complexes. HDAC inhibition was able to reverse this process by downregulation of Id2. Furthermore, treatment of pregnant Pkd1 mice with trichostatin A prevented cyst formation in the developing embryonic kidneys, showing that this inhibition is effective in vivo during early cyst formation. Thus, HDAC inhibition targets Id2-mediated pathways to downregulate cystic epithelial cell proliferation and hence cystogenesis.
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