Sirt1 regulates canonical TGF-β signalling to control fibroblast activation and tissue fibrosis

Zerr, Pawel; Palumbo‐Zerr, Katrin; Huang, Junlong; Tomčík, Michal; Šumová, Barbora; Distler, Oliver; Schett, Georg; Distler, Jörg H W

doi:10.1136/annrheumdis-2014-205740

Cited by 115 publications

(91 citation statements)

References 50 publications

(42 reference statements)

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“…SIRT1 has been reported to deacetylate the lysine residues of a number of nuclear proteins, such as p53 (Yuan et al., 2011), NF‐κB (Salminen & Kaarniranta, 2009), PGC‐1a (Amat et al., 2009), CBP/p300 (Das, Lucia, Hansen & Tyler, 2009), and forkhead family proteins (Brunet et al., 2004). Several recent studies demonstrated that Sirt1 could inhibit TGF‐β signaling and ameliorate fibrosis (Huang et al., 2014; Kume et al., 2007; Zerr et al., 2014). In this study, we found that aging suppressed SIRT1 activity, increased TGFβ and MMP expressions, and induced fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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Summary DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice.

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Section: Discussionmentioning

confidence: 99%

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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“…In supporting this hypothesis, SIRT1 is found to suppress the expression of protein tyrosine phosphatase 1B (Sun et al, 2007;Gagarina et al, 2010), a member of the dephosphorylating protein family, which negatively regulates the activity of growth signaling molecules including EGFR and PDGFRb (Gu et al, 2003;Ponnusamy et al, 2013). Nevertheless, we cannot rule out the possibility that SRT1720 can also stimulate renal fibrosis through stimulation of TGF-b signaling activation because it has been reported that activation of SIRT1 increased Smad reporter activity, enhanced transcription of TGF-b target genes, and promoted release of collagen, whereas knockdown of SIRT1 inhibited TGF-b/SMAD signaling and reduced collagen release in skin fibroblasts (Zerr et al, 2014). Further experiments are needed to examine the role of SIRT1 in the regulation of this signaling pathway in renal interstitial fibroblasts.…”

Section: Discussionmentioning

confidence: 96%

Activation of Sirtuin-1 Promotes Renal Fibroblast Activation and Aggravates Renal Fibrogenesis

Ponnusamy

Zhuang

Zhou

et al. 2015

J Pharmacol Exp Ther

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Although activation of sirtuin-1 (SIRT1) has been shown to protect the kidney from acute injury, its role in renal fibrosis remains controversial since both inhibition and activation of SIRT1 have been reported to attenuate renal fibrosis. To resolve this conflict, we further examined the effect of SIRT1 activators on the activation of renal interstitial fibroblasts and development of renal fibrosis in vivo and in vitro. In a murine model of renal fibrosis induced by unilateral ureteral obstruction, administration , another SIRT1 activator, also resulted in enhanced expression of a-SMA and fibronectin. Mechanistic studies showed that augmentation of renal fibrogenesis by SRT1720 is associated with elevated phosphorylation of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor b (PDGFRb). SRT1720 treatment also increased the phosphorylation of signal transducer and activator of transcription 3 and protein kinase B in the fibrotic kidney and NRK-49F cells. However, SRT1720 treatment did not affect expression of proliferating cell nuclear protein, a proliferation marker and activation of extracellular signal regulated kinase 1/2 in vitro and in vivo. These results indicate that SIRT1-activating compounds can provoke renal fibrogenesis through a mechanism involved in the activation of EGFR and PDGFR signaling pathways and suggest that long-term use of SIRT1 activators risks the development and progression of chronic kidney disease.

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“…During the progression of IPF, the chronic injuries incite the abnormally activated alveolar epithelial cells (AECs) to secrete TGF-β, which in turn promotes the EMT, by which AECs undergo mesenchymal transformation, lose their cell-cell adhesion, acquire migratory and invasive properties, and ultimately convert into mesenchymal cells, accounting for excessive deposition of ECM in parenchymal . TGF-β signaling is essential in a number of profibrotic events including EMT, fibroblast activation and eventual ECM deposition (Yang et al 2014;Eberlein et al 2015;Okumura et al 2015;Zerr et al 2016). Sunitinib profoundly inhibited TGF-β-induced EMT (Fig.…”

Section: Discussionmentioning

confidence: 97%

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

Huang

Wang

Yuan

et al. 2016

Tohoku J. Exp. Med.

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Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. IPF is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition (EMT). However, there is still a lack of strategies to target EMT for the treatment of IPF. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin (BLM). Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells (HBEs) and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-β, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-β in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.

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Sirt1 regulates canonical TGF-β signalling to control fibroblast activation and tissue fibrosis

Cited by 115 publications

References 50 publications

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Activation of Sirtuin-1 Promotes Renal Fibroblast Activation and Aggravates Renal Fibrogenesis

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

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