Valproic acid attenuates renal fibrosis through the induction of autophagy

Kawaoka, Koichiro; Doi, Shigehiro; Nakashima, Ayumu; Yamada, Kyoko; Ueno, Toshinori; Doi, Toshiki; Takao, Masaki

doi:10.1007/s10157-016-1365-6

Cited by 31 publications

(29 citation statements)

References 36 publications

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“…In addition, anti-fibrotic effects of valproic acid, an inhibitor of class I HDACs, have been reported in experimental models of numerous fibrotic conditions 157 . This drug suppresses TGFβ1-stimulated αSMA expression, probably by modulating SMAD expression, and is a potent inducer of autophagy 158,159 . More recently, several compounds with selectivity for individual HDACs, including HDAC1, HDAC3, HDAC6 and HDAC8, have been described 160 .…”

Section: Targets and Therapeutic Interventions For Epigenetic Changesmentioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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Section: Targets and Therapeutic Interventions For Epigenetic Changesmentioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

View full text Add to dashboard Cite

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“…Renal interstitial fibrosis is an inevitable outcome of all causes of progressive chronic kidney disease (CKD). EMT (Pang et al, 2016), chronic inflammation (Xiao et al, 2017), oxidative stress (Qin et al, 2016), and autophagy (Kawaoka et al, 2016) are reported to be key mechanisms in the pathogenesis and progression of renal interstitial fibrosis. To study renal fibrosis in vivo and in vitro, UUO and To preliminarily explore which aspects of LncRNA 74.1 exactly exerted its functional role, the markers of inflammation (IL-6, TNF-α, MCP-1), EMT (α-SMA, E-cadherin, and vimentin), oxidative stress resistance (NQO1, HO-1) and autophagy (Atg5, Atg7, and becilin 1) were all detected in LncRNA 74.1 gain-of-function HK-2 cells with or without TGF-β treatment.…”

Section: Discussionmentioning

confidence: 99%

LncRNA ENST00000453774.1 contributes to oxidative stress defense dependent on autophagy mediation to reduce extracellular matrix and alleviate renal fibrosis

Xiao

Yuan

Chen

et al. 2018

Journal Cellular Physiology

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Although long noncoding RNA (LncRNA) are important players in the initiation and progression of many pathological processes, the role of LncRNAENST00000453774.1 (LncRNA 74.1) in renal fibrosis still remains unclear. Lentivirus mediated LncRNA 74.1 overexpressing HK2 cells and overexpression mice models were constructed. HK2 cells induced by transforming growth factor‐β (TGF‐β) in vitro, and the mice UUO model in vivo were used to simulate renal fibrosis. The expression of LncRNA 74.1 was significantly downregulated in the TGF‐β‐induced HK‐2 cell fibrosis and clinical renal fibrosis specimens. LncRNA 74.1 overexpression obviously attenuated renal fibrosis in vitro and unilateral ureteral obstruction‐induced renal fibrosis in vivo. LncRNA 74.1 promoted reactive oxygen species defense by activating prosurvival autophagy then decreased ECM‐related proteins fibronectin and collagen I involved in renal fibrosis. We also found that Nrf2‐keap1 signaling played important roles in the remission of ECM mediated by LncRNA 74.1. This study indicates that LncRNA 74.1 downregulation would contribute to renal fibrosis and its overexpression might represent a novel anti‐fibrotic treatment in renal diseases.

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“…On the basis targets of energy regulation, we can identify agents that regulate energy metabolism, such as insulin, adiponectin, and glucagon, during the process of autophagy and then change the balance of autophagy‐associated chemical reactions . Although the expression of ATGs and the formation of phagosomes are rarely influenced by these agents, they significantly change the speed and efficiency of autophagy . Furthermore, the majority of modulators targeting autophagy affect the process of autophagy induction.…”

Section: Autophagy‐associated Modulatorsmentioning

confidence: 99%

“…[282][283][284][285] Although the expression of ATGs and the formation of phagosomes are rarely influenced by these agents, they significantly change the speed and efficiency of autophagy. 286 Furthermore, the majority of modulators targeting autophagy affect the process of autophagy induction. For example, 3-MA is a phosphoinositide-3kinase (PI3K/VPS34) inhibitor widely used to suppress autophagy in basic studies, and rapamycin is an inhibitor of mTOR that leads to the formation of the autophagy initiation complex and then activates ULK1 to induce autophagy.…”

Section: Autophagy-associated Modulatorsmentioning

confidence: 99%

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

Sui

Zhang

et al. 2019

Medicinal Research Reviews

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Autophagy is central to the maintenance of intracellular homeostasis across species. Accordingly, autophagy disorders are linked to a variety of diseases from the embryonic stage until death, and the role of autophagy as a therapeutic target has been widely recognized. However, autophagy‐associated therapy for human diseases is still in its infancy and is supported by limited evidence. In this review, we summarize the landscape of autophagy‐associated diseases and current autophagy modulators. Furthermore, we investigate the existing autophagy‐associated clinical trials, analyze the obstacles that limit their progress, offer tactics that may allow barriers to be overcome along the way and then discuss the therapeutic potential of autophagy modulators in clinical applications.

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Valproic acid attenuates renal fibrosis through the induction of autophagy

Abstract: These findings suggest that VPA may be a candidate drug for the treatment of renal fibrosis through the induction of autophagy.

Cited by 31 publications

References 36 publications

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

LncRNA ENST00000453774.1 contributes to oxidative stress defense dependent on autophagy mediation to reduce extracellular matrix and alleviate renal fibrosis

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

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