Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

Xu, Lei; Liu, Na; Gu, Hang; Wang, Hongrui; Shi, Yingfeng; Ma, Xiaoyan; Ma, Shuping; Ni, Jun; Tao, Min; Qiu, Andong; Zhuang, Songlin

doi:10.18632/oncotarget.20982

Cited by 29 publications

(37 citation statements)

References 54 publications

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“…To our knowledge, our study first deals on the effect of HDAC1 inhibition on MMT of MCs. A recent report analyzed the role of a selective HDAC6 inhibitor, tubastatin, in the inhibition of peritoneal MMT and fibrosis 29 . Interestingly, in apparent contradiction to our results, treatment with the inhibitor of histone acetyltransferase C646 was reported to limit the MMT induced by glucose in a MC line 30 .…”

Section: Discussionmentioning

confidence: 99%

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

Rossi

Battistelli

Turris

et al. 2018

Sci Rep

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Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Aim of this study was to evaluate possible effects of histone deacetylase (HDAC) inhibitors, key components of the epigenetic machinery, in counteracting MMT observed in MCs isolated from effluent of PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While the effect of other inhibitors was limited to a partial E-cadherin re-expression, MS-275, a HDAC1-3 inhibitor, promoted: (i) downregulation of mesenchymal markers (MMP2, Col1A1, PAI-1, TGFβ1, TGFβRI) (ii) upregulation of epithelial markers (E-cadherin, Occludin), (iii) reacquisition of an epithelial-like morphology and (iv) marked reduction of cellular invasiveness. Results were confirmed by HDAC1 genetic silencing. Mechanistically, MS-275 causes: (i) increase of nuclear histone H3 acetylation (ii) rescue of the acetylation profile on E-cadherin promoter, (iii) Snail functional impairment. Overall, our study, pinpointing a role for HDAC1, revealed a new player in the regulation of peritoneal fibrosis, providing the rationale for future therapeutic opportunities.

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Section: Discussionmentioning

confidence: 99%

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

Rossi

Battistelli

Turris

et al. 2018

Sci Rep

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“…We have previously demonstrated that inhibition of class I HDACs with MS-275 or of Sirt1 and 2 with sirtinol inhibits renal fibroblast activation and attenuates renal fibrosis (23,24). Recently, studies in our laboratories and others have also indicated that the administration of tubastatin A, a selective inhibitor of HDAC6, was effective in blocking peritoneal and renal fibrosis (25,26). Moreover, Wang et al (27) have shown that HDAC4, an isoform of class IIa HDACs, contributes to podocyte injury in a murine model of diabetic nephropathy.…”

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confidence: 99%

Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis

et al. 2019

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In this study, we examined the effect of MC1568, a selective class IIa histone deacetylase (HDAC) inhibitor, on the development and progression of renal fibrosis in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO). All 4 class IIa HDAC isoforms, in particular HDAC4, were up‐regulated in renal epithelial cells of the injured kidney. Administration of MC1568 immediately after UUO injury reduced expression of α–smooth muscle actin (α‐SMA), fibronectin, and collagen 1. MC1568 treatment or small interfering RNA–mediated silencing of HDAC4 also suppressed expression of those proteins in cultured renal epithelial cells. Mechanistically, MC1568 abrogated UUO‐induced phosphorylation of Smad3, NF‐κB, and up‐regulation of integrin a Vβ6 in the kidney and inhibited TGF‐β1‐induced responses in cultured renal epithelial cells. MCI568 also increased renal expression of klotho, bone morphogenetic protein 7, and Smad7. Moreover, delayed administration of MC1568 at 3 d after ureteral obstruction reversed the expression of α‐SMA, fibronectin, and collagen 1 and increased expression of matrix metalloproteinase (MMP)‐2 and ‐9. Collectively, these results suggest that selectively targeting class IIa HD AC isoforms (in particular HDAC4) may inhibit development and progression of renal fibrosis by suppressing activation and expression of multiple prof ibrotic molecules and increasing expression of antif ibrotic proteins and MMPs.—Xiong, C., Guan, Y., Zhou, X., Liu, L., Zhuang, M. A., Zhang, W., Zhang, Y., Masucci, M. V., Bayliss, G., Zhao, T. C., Zhuang, S. Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis. FASEB J. 33,8249–8262 (2019). http://www.fasebj.org

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“…Research groups have linked HDAC6 overexpression to organ fibrosis including the lung, kidney, and peritoneum (37,38). TGF β/Smad signaling is a key player in regulating renal fibrosis via the activation of Smad2 and Smad3 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…TGF β1induced epithelial mesenchymal transition is associated with HDAC6 dependent deacetylation of α tubulin (40,41). HDAC6 silencing inhibits TGF β1 induced E cadherin loss and collagen I expression (38). Korfei and colleagues (37) suggested that upregulation of HDAC6 in idiopathic pulmonary fibrosis was associated with fibroblast proliferation, fibroblast to myofibroblast differentiation and myofibroblast resistance to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse

2020

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Introduction: Lupus nephritis (LN) is a substantial manifestation of systemic lupus erythematosus (SLE). HDAC6 is overexpressed in various kidney diseases, and its inhibition slows kidney injury progression. Urinary TFF3 increases in chronic kidney diseases (CKDs) and may be associated with patient's outcome.Objectives: This study aimed to examine the relationship between renal HDAC6 and TFF3 proteins expression and with clinicopathologic characteristics and outcome of LN. Patients and Methods: HDAC6 and TFF3 proteins' expression was immunohistochemically detected in 56 cases of LN. They were correlated to patients' age, gender, urinary 24 hours protein and serum creatinine levels at baseline and during follow up. Additionally, they were correlated to LN classes, activity index (AI) and chronicity index (CI) and relapse free survival (RFS). Results: HDAC6 overexpression was significantly associated with serum creatinine and 24 hours proteinuria levels at baseline (P = 0.041 and P =0.026 respectively) and during follow up (P < 0.001). It was associated with AI and CI of class III and IV LN (P = 0.047 and 0.003 respectively). TFF3 overexpression was associated with higher serum creatinine and more proteinuria at baseline (P = 0.015 and 0.001 respectively) and during follow up (P < 0.001). It was significantly associated with higher CI (P = 0.001). Both markers were associated with shorter RFS (P < 0.001). Conclusion: HDAC6 and TFF3 proteins are associated with clinicopathologic features of renal damage in LN. They are reliable predictors of patients' RFS, which makes them good candidates for risk stratification of patients and targeted therapy. ABSTRACT Implication for health policy/practice/research/medical education:Lupus nephritis is a leading cause of CKD, so it is crucial to search for markers that could predict tubulointerstitial injury and patients' relapses. HDAC6 and TFF3 are associated with features of renal damage and early relapse of LN. These effects are due to their capacity to up-regulate BCL2 expression promoting survival of autoreactive B cells as well as stimulation of persistent release of inflammatory cytokines by dendritc cells. Therefore, HDAC6 & TFF3 can be used for prognostic stratification of LN patients. Please cite this paper as: Abdelbary EH, Farouk Ahmed N, Abdelmohsen Ghorab A. Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse. J Nephropathol. 2020;9(2):e14.

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Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

Cited by 29 publications

References 54 publications

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis

Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse

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