Tubastatin A suppresses renal fibrosis via regulation of epigenetic histone modification and Smad3-dependent fibrotic genes

Choi, Sin Young; Ryu, Yuhee; Kee, Hae Jin; Cho, Soo-Na; Kim, Gwi Ran; Cho, Jae Yeong; Kim, Hyung-Seok; Kim, Inkyeom; Jeong, Myung Ho

doi:10.1016/j.vph.2015.04.006

Cited by 68 publications

(52 citation statements)

References 43 publications

(47 reference statements)

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“…This finding indicates that piceatannol may be considered to be acting a dietary HDAC inhibitor rather than a HDAC activator in this model. As mentioned above, our findings are supported by several studies showing that renal fibrosis was attenuated by the pan-HDAC inhibitor TSA [57], class I HDAC inhibitor MS-275 [56], and HDAC6-selective inhibitor Tubastatin A [16]. …”

Section: Discussionsupporting

confidence: 87%

“…For example, class I HDACs are activated in transforming growth factor β1- (TGF-β1) treated kidney epithelial cells [13] and are involved in the development of EMT and the ECM in fibrosis with [14] or without [15] diabetes. HDAC6, a class IIb HDAC, may be a target for hypertension-induced kidney fibrosis [16]. Class IIa HDACs (HDAC4/5/7) are related to diabetes-induced fibrosis [17].…”

Section: Introductionmentioning

confidence: 99%

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Piceatannol Attenuates Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Downregulation of Histone Deacetylase 4/5 or p38-MAPK Signaling

et al. 2016

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Piceatannol, a resveratrol metabolite, is a phenolic compound found in red wine and grapes. We investigated the effect of piceatannol on renal fibrosis and histone deacetylase (HDAC) expression in a mouse model of unilateral ureteral obstruction (UUO). Fibrosis was established by UUO and piceatannol was intraperitoneally injected for 2 weeks. Piceatannol suppressed extracellular matrix (ECM) protein deposition including collagen type I and fibronectin as well as connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA) in UUO kidneys. However, the expressions of epithelial-mesenchymal transition (EMT) marker genes, such as N-cadherin and E-cadherin, were not changed in the kidneys after UUO. Masson’s trichrome staining and fluorescence immunostaining showed that piceatannol administration attenuated collagen deposition in UUO kidneys. HDAC1, HDAC4, HDAC5, HDAC6, and HDAC10 protein expression was upregulated in UUO kidneys, whereas that of HDAC8 was downregulated. Piceatannol treatment significantly reduced HDAC4 and HDAC5 protein expression. Further, piceatannol attenuated phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) in UUO kidneys, but not that of transforming growth factor beta1-Smad2/3. These results suggest that class I HDACs and class IIa/b HDACs are involved in renal fibrosis development. Piceatannol may be a beneficial therapeutic agent for treating renal fibrosis via reduction of HDAC4 and HDAC5 protein expression or suppression of the p38-MAPK signaling pathway.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Piceatannol Attenuates Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Downregulation of Histone Deacetylase 4/5 or p38-MAPK Signaling

et al. 2016

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“…This finding suggests that HDAC8 enzyme activity is not required for ECM production. Recently, we reported that tubastatin A, an HDAC6‐selective inhibitor, suppresses renal fibrosis . Therefore, we cannot rule out the possible relevance of HDAC6, 7 and 9 in the accumulation of ECM proteins in HK2 cells.…”

Section: Discussionmentioning

confidence: 94%

Class I HDACs specifically regulate E‐cadherin expression in human renal epithelial cells

Choi

Kee

Kurz

et al. 2016

J Cellular Molecular Medi

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Epithelial‐mesenchymal transition (EMT) and renal fibrosis are closely involved in chronic kidney disease. Inhibition of histone deacetylase (HDAC) has an anti‐fibrotic effect in various diseases. However, the pathophysiological role of isoform‐specific HDACs or class‐selective HDACs in renal fibrosis remains unknown. Here, we investigated EMT markers and extracellular matrix (ECM) proteins in a human proximal tubular cell line (HK‐2) by using HDAC inhibitors or by knockdown of class I HDACs (HDAC1, 2, 3 and 8). Trichostatin A (TSA), MS275, PCI34051 and LMK235 inhibited ECM proteins such as collagen type I or fibronectin in transforming growth factor β1 (TGF‐β1)‐induced HK2 cells. However, restoration of TGF‐β1‐induced E‐cadherin down‐regulation was only seen in HK‐2 cells treated with TSA or MS275, but not with PCI34051, whereas TGF‐β1‐induced N‐cadherin expression was not affected by the inhibitors. ECM protein and EMT marker levels were prevented or restored by small interfering RNA transfection against HDAC8, but not against other class I HDACs (HDAC1, 2 and 3). E‐cadherin regulation is mediated by HDAC8 expression, but not by HDAC8 enzyme activity. Thus, class I HDACs (HDAC1, 2, 3 and 8) play a major role in regulating ECM and EMT, whereas class IIa HDACs (HDAC4 and 5) are less effective.

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“…Blood pressure measurements were obtained as described previously 15). Briefly, the systolic blood pressure, diastolic blood pressure, and mean blood pressure were measured in conscious state by the tail-cuff method (Visitech Systems, BP-2000, Apex, NC, USA).…”

Section: Methodsmentioning

confidence: 99%

Expression of Class I and Class II a/b Histone Deacetylase is Dysregulated in Hypertensive Animal Models

et al. 2017

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Background and ObjectivesDysregulation of histone deacetylase expression and enzymatic activity is associated with a number of diseases. It has been reported that protein levels of histone deacetylase (HDAC)1 and HDAC5 increase during human pulmonary hypertension, and that the enzymatic activity of HDAC6 is induced in a chronic hypertensive animal model. This study investigated the protein expression profiles of class I and II a/b HDACs in three systemic hypertension models.Subjects and MethodsWe used three different hypertensive animal models: (i) Wistar-Kyoto rats (n=8) and spontaneously hypertensive rats (SHR; n=8), (ii) mice infused with saline or angiotensin II to induce hypertension, via osmotic mini-pump for 2 weeks, and (iii) mice that were allowed to drink L-NG-nitro-L-arginine methyl ester (L-NAME) to induce hypertension.ResultsSHR showed high systolic, diastolic, and mean blood pressures. Similar increases in systolic blood pressure were observed in angiotensin II or L-NAME-induced hypertensive mice. In SHR, class IIa HDAC (HDAC4, 5, and 7) and class IIb HDAC (HDAC6 and 10) protein expression were significantly increased. In addition, a HDAC3 protein expression was induced in SHR. However, in L-NAME mice, class IIa HDAC protein levels (HDAC4, 5, 7, and 9) were significantly reduced. HDAC8 protein levels were significantly reduced both in angiotensin II mice and in SHR.ConclusionThese results indicate that dysregulation of class I and class II HDAC protein is closely associated with chronic hypertension.

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Tubastatin A suppresses renal fibrosis via regulation of epigenetic histone modification and Smad3-dependent fibrotic genes

Cited by 68 publications

References 43 publications

Piceatannol Attenuates Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Downregulation of Histone Deacetylase 4/5 or p38-MAPK Signaling

Piceatannol Attenuates Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Downregulation of Histone Deacetylase 4/5 or p38-MAPK Signaling

Class I HDACs specifically regulate E‐cadherin expression in human renal epithelial cells

Expression of Class I and Class II a/b Histone Deacetylase is Dysregulated in Hypertensive Animal Models

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