ArticleCell death and differentiation2021
Histone deacetylase 3 aberration inhibits Klotho transcription and promotes renal fibrosis.
Article in Cell death and differentiation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 80 citations in OpenAlex.
- Histone deacetylase 3‑mediated histone deacetylation combined with activating transcription factor 3 promotes renal fibrosis by inhibiting Klotho.Molecular medicine reports · 2026Article
- The histone deacetylase family in health and disease.Signal transduction and targeted therapy · 2026Review
- Pharmacological targeting of kidney fibrosis: druggable mechanisms, translational models, and emerging antifibrotic therapies.Clinical kidney journal · 2026Review
- The impactful role of the HDACs in the regulation of gene expression and as targets for disease therapy.Science advances · 2026Review
- BRD4 Inhibition alleviates sepsis-associated acute kidney injury via suppression of NOX4-mediated oxidative stress and inflammation.Cell death discovery · 2026Article
- Epigenetic Suppression of RASAL1 by HDAC3 and Cofactor YY1 Promotes Fibroblast-Myofibroblast Transition and Renal Fibrosis.Research (Washington, D.C.) · 2026Article
- Sphingomyelin regulates astrocyte activity by regulating NF-κB signaling via HDAC1/3 expression.Journal of lipid research · 2025Article
- Emerging epigenetic modifications in renal fibrosis: From mechanisms to treatments.Acta pharmaceutica Sinica. B · 2025Review
- Role of nuclear receptors, lipid metabolism, and mitochondrial function in the pathogenesis of diabetic kidney disease.American journal of physiology. Renal physiology · 2025Review
- Histone deacetylases and their inhibitors in kidney diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Contribution of histone deacetylases (HDACs) to the regulation of histone and non-histone proteins: implications for fibrotic diseases.BMB reports · 2025Review
- Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study.International urology and nephrology · 2025Observational
- Enhancement of angiotensin II type 1 receptor-associated protein suppresses kidney inflammation in a mouse model of aristolochic acid nephropathy.Scientific reports · 2025Article
- The Impact of Klotho in Cancer: From Development and Progression to Therapeutic Potential.Genes · 2025Review
- HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis.Frontiers in pharmacology · 2025Article
- Enzymatic post-translational modifications of proteins in chronic kidney disease: mechanisms, regulation, and clinical significance.Frontiers in pharmacology · 2025Review
- Targeting ferroptosis: novel therapeutic approaches and intervention strategies for kidney diseases.Frontiers in immunology · 2025Review
- Succinate Facilitates CD4Journal of inflammation research · 2025Article
- Inflammation-Induced Klotho Deficiency: A Possible Key Driver of Chronic Kidney Disease Progression.International journal of general medicine · 2025Review
- Acetylation in renal physiology and pathophysiology.Frontiers in pharmacology · 2025Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Development of renal fibrosis is a hallmark of renal aging and chronic kidney disease of all etiologies and characterized by extensive renal cell injuries and subsequent myofibroblast transdifferentiations (MTDs), which are significantly influenced by aberrant histone deacetylase (HDAC) activities. However, the key HDAC isoforms and effectors that are causally involved in the processes remain poorly understood. Here, we report that aberrant HDAC3 induction and its inhibition of Klotho, a renal epithelium-enriched aging suppressor, contribute significantly to renal fibrogenesis. HDAC3 was preferentially elevated with concomitant Klotho suppression in fibrotic kidneys incurred by unilateral ureter obstruction (UUO) and aristolochic acid nephropathy (AAN), whereas Hdac3 knockout resisted the fibrotic pathologies. The HDAC3 elevation is substantially blocked by the inhibitors of TGFβ receptor and Smad3 phosphorylation, suggesting that TGFβ/Smad signal activates Hdac3 transcription. Consistently, an HDAC3-selective inhibitor RGFP966 derepressed Klotho and mitigated the renal fibrotic injuries in both UUO and AAN mice. Further, HDAC3 overexpression or inhibition in renal epithelia inversely affected Klotho abundances and HDAC3 was inducibly associated with transcription regulators NCoR and NF-kB and bound to Klotho promoter in fibrotic kidney, supporting that aberrant HDAC3 targets and transcriptionally inhibits Klotho under renal fibrotic conditions. More importantly, the antirenal fibrosis effects of RGFP966 were largely compromised in mice with siRNA-mediated Klotho knockdown. Hence, HDAC3 aberration and the subsequent Klotho suppression constitute an important regulatory loop that promotes MTD and renal fibrosis and uses of HDAC3-selective inhibitors are potentially effective in treating renal fibrotic disorders.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.