Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy

Pang, Maoyin; Kothapally, Jagan; Mao, Haiping; Tolbert, Evelyn; Ponnusamy, Murugavel; Chin, Y. Eugene; Zhuang, Songlin

doi:10.1152/ajprenal.00282.2009

Cited by 191 publications

(225 citation statements)

References 54 publications

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“…[22][23][24] In the present study, treatment of PD fibroblasts with TGF-b1 induced fibroblast-to-myofibroblast transition, as evidenced by both Western blot analysis and immunocytochemical staining for smooth muscle aactin. Similar to a previous study that showed a decrease in the mRNA expression of smooth muscle a-actin in renal tubular epithelial cells when HDAC2 was knocked down, 16 inhibition of HDAC2 abrogated TGF-b1-induced transdifferentiation of PD fibroblasts into myofibroblasts.…”

Section: Discussionsupporting

confidence: 55%

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Ryu¹,

Kim²,

Choi³

et al. 2013

Asian J Androl

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Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-b1 (TGF-b1). Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle a-actin and extracellular matrix proteins, including plasminogen activator inhibitor-1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-b1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-b1-induced extracellular matrix production by blocking TGF-b1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-b1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD.

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Section: Discussionsupporting

confidence: 55%

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Ryu¹,

Kim²,

Choi³

et al. 2013

Asian J Androl

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“…Captopril, an ACEI, has been widely used to treat patients with kidney diseases, 14 whereas trichostatin A or vorinostat, which are both HDACIs, have been recently shown to improve the status of kidney fibrosis in animal models of kidney diseases; 15 thus, we decided to focus on these two drugs. On the basis of our prior clinical and pharmacological understanding, other combinations among the top 10 are less likely to have renal protection, so we did not pursue them first.…”

Section: Prediction Of Drug Combinations That Could Reverse Gene Exprmentioning

confidence: 99%

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Zhong

Chen

Liu

et al. 2013

Journal of the American Society of Nephrology

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The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice). We predicted that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a histone deacetylase inhibitor would maximally reverse the disease-associated expression of genes in the kidneys of these mice. Testing the combination of these inhibitors in Tg26 mice revealed an additive renoprotective effect, as suggested by reduction of proteinuria, improvement of renal function, and attenuation of kidney injury. Furthermore, we observed the predicted treatment-associated changes in the expression of selected genes and pathway components. In summary, these data suggest that the combination of an ACE inhibitor and a histone deacetylase inhibitor could have therapeutic potential for various kidney diseases. In addition, this study provides proof-of-concept that drug-induced expression signatures have potential use in predicting the effects of combination drug therapy.

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“…STAT3 has previously been considered to be involved in promoting cell cycle progression and cellular transformation and in preventing apoptosis [23,24] . Increasing evidence suggests that STAT3 can be activated and highly expressed during the progression of fibrogenesis in the obstructed kidney [25][26][27] and under other pathophysiological circumstances [9] . Despite being one of the major mediators of transforming growth factor-β1 (TGF-β1)-driven kidney dysfunction [27][28][29] , the role of Ang II-induced STAT3 signaling in renal fibrogenesis remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

Shen

Wang

et al. 2014

Acta Pharmacol Sin

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Aim: To explore the relationship between the signal transducer and activator of transcription 3 (STAT3) signaling and renal fibrosis. Methods: Rat renal tubular epithelial NRK-52E cells were treated with angiotensin II (Ang II), nicotinamide (an inhibitor of NAD + -dependent class III protein deacetylases, SIRT1-7), or resveratrol (an activator of SIRT1). Mice underwent unilateral ureteral obstruction (UUO) were used for in vivo studies. Renal interstitial fibrosis was observed with HE and Masson's trichrome staining. STAT3 acetylation and phosphorylation, fibronectin, collagen I, collagen IV, and α-smooth muscle actin (α-SMA) levels were examined using Western blotting. Results: Nicotinamide (0.625-10 mmol/L) dose-dependently increased STAT3 acetylation on Lys685 and phosphorylation on Tyr705 in NRK-52E cells, accompanied by accumulation of fibronectin and collagen IV. Ang II increased STAT3 phosphorylation on Tyr705 and the expression of fibronectin, collagen IV and α-SMA in the cells. Pretreatment with resveratrol (12.5 μmol/L) blocked Ang II-induced effects in the cells. UUO induced marked STAT3 phosphorylation, fibronectin, collagen IV and α-SMA accumulation, and renal interstitial fibrosis in the obstructed kidneys, which were significantly attenuated by daily administration of resveratrol (100 mg/kg). Conclusion: STAT3 acetylation plays an important role in activation of STAT3 signaling pathway and consequent renal fibrosis.

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Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy

Cited by 191 publications

References 54 publications

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

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