Histone deacetylase inhibitor restores surfactant protein-C expression in alveolar-epithelial type II cells and attenuates bleomycin-induced pulmonary fibrosis<i>in vivo</i>

Ota, Chiharu; Yamada, Mitsuhiro; Fujino, Naoya; Motohashi, Hozumi; Tando, Yukiko; Takei, Yusuke; Suzuki, Takaya; Takahashi, Toru; Kamata, Satoshi; Makiguchi, Tomonori; Yamaya, Mutsuo; Kubo, Hiroshi

doi:10.3109/01902148.2015.1060275

Cited by 46 publications

(39 citation statements)

References 43 publications

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“…Epigenetic mechanisms are well known to play a key role in fibrosis (Helling and Yang, 2015;Page and Mann, 2015;Yang and Schwartz, 2015). Specifically in pulmonary fibrosis and fibroblast biology, changes in DNA methylation (Huang et al, 2014;Qu et al, 2018;Sanders et al, 2012;Yang et al, 2014), microRNAs (Khalil et al, 2015;Liu et al, 2010;Miao et al, 2018;Yang et al, 2013) and histone-modifying enzymes (Bai et al, 2019;Bombardo et al, 2018;Conforti et al, 2017;Coward et al, 2014Coward et al, , 2009Glenisson et al, 2007;Hemmatazad et al, 2009;Khalil et al, 2015;Korfei et al, 2015;Ota et al, 2015;Sanders et al, 2014Sanders et al, , 2017 have been shown to accompany and drive lung fibroblast activation and disease progression. Our screen interrogated the effects of a multitude of epigenetic-modifying small molecules, and identified effects of a variety of epigenetic writers, erasers and readers, demonstrating the complexity and importance of epigenetic regulators in controlling fibroblast biology.…”

Section: Discussionmentioning

confidence: 99%

“…BRD4) (Tang et al, 2013) and EZH2 (Coward et al, 2018;Xiao et al, 2016) were identified. We chose to focus on pracinostat because it was most effective in our primary assay outcome, and because HDAC inhibition has proven effective in fibrosis models (Barter et al, 2010;Bombardo et al, 2018;Conforti et al, 2017;Glenisson et al, 2007;Guo et al, 2009;Kang et al, 2017;Khalil et al, 2015;Kim et al, 2018;Ota et al, 2015) but its anti-fibrotic effects remain poorly understood. However, we also note that inhibitors of several enzymes not previously linked to fibrosis were identified in our screen, such as L3MBTL3, a reader of methylated-lysine on histones (Min et al, 2007;Trojer et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Jones

Haak

Caporarello

et al. 2019

Journal of Cell Science

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Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβmediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene PPARGC1A (PGC1α) in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose siRNA-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together, these results provide novel mechanistic insight into the essential role HDACs play in TGFβmediated fibroblast activation via targeted gene repression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Jones

Haak

Caporarello

et al. 2019

Journal of Cell Science

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“…Early Transcriptional Changes in Arl13b flox/flox ; Ksp-Cre Mice Because HDACIs have been shown to suppress fibrosis, including renal fibrosis, [27][28][29][30][31][32][33][34][35][36][37] we investigated the effect of VPA treatment on fibrosis in Arl13b flox/flox ; Ksp-Cre mice. VPA treatment from P10 to P25 significantly reduced collagen deposition in mutant mice as shown by trichrome staining ( Figure 5G).…”

Section: Vpa Treatment Ameliorates Fibrosis and Suppressesmentioning

confidence: 99%

Deletion of ADP Ribosylation Factor-Like GTPase 13B Leads to Kidney Cysts

Li¹,

Tian

et al. 2016

JASN

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The gene for ADP ribosylation factor-like GTPase 13B (Arl13b) encodes a small GTPase essential for cilia biogenesis in multiple model organisms. Inactivation of arl13b in zebrafish leads to a number of phenotypes indicative of defective cilia, including cystic kidneys. In mouse, null mutation in Arl13b results in severe patterning defects in the neural tube and defective Hedgehog signaling. Human mutations of ARL13B lead to Joubert syndrome, a ciliopathy. However, patients with mutated ARL13B do not develop kidney cysts. To investigate whether Arl13b has a role in ciliogenesis in mammalian kidney and whether loss of function of Arl13b leads to cystic kidneys in mammals, we generated a mouse model with kidney-specific conditional knockout of Arl13b Deletion of Arl13b in the distal nephron at the perinatal stage led to a cilia biogenesis defect and rapid kidney cyst formation. Additionally, we detected misregulation of multiple pathways in the cystic kidneys of this model. Moreover, valproic acid, a histone deacetylase inhibitor that we previously showed slows cyst progression in a mouse cystic kidney model with neonatal inactivation of Pkd1, inhibited the early rise of Wnt7a expression, ameliorated fibrosis, slowed cyst progression, and improved kidney function in the Arl13b mutant mouse. Finally, in rescue experiments in zebrafish, all ARL13B allele combinations identified in patients with Joubert syndrome provided residual Arl13b function, supporting the idea that the lack of cystic kidney phenotype in human patients with ARL13B mutations is explained by the hypomorphic nature of the mutations.

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“…This response, termed mitohormesis, is being rapidly dissected in many model systems and must be considered in the design of all mitochondrial-targeted therapeutics for the treatment of lung disease (66). Other mitochondrial-targeted therapeutic strategies that could potentially be used to treat lung diseases include the use of metabolic modulating compounds such as dicholoroacetate (138), histone deacetylase inhibitors (139,140), and fission inhibitors. Stimulating adaptive mitochondrial biogenesis and mitophagy may be a useful adjuvant therapy for ALI in sepsis (44), and transfer of mitochondria from bone marrowderived mesenchymal stem cells to injured alveolar epithelium may be beneficial in ARDS, asthma, or COPD (141).…”

Section: Mtdampsmentioning

confidence: 99%