Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney

Sakao, Yukitoshi; Kato, Akihiko; Tsuji, Takayuki; Yasuda, Hideo; Togawa, Akashi; Fujigaki, Yoshihide; Kahyo, Tomoaki; Setou, Mitsutoshi; Hishida, Akira

doi:10.1007/s10157-011-0421-5

Cited by 21 publications

(21 citation statements)

References 32 publications

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“…As a transcriptional repressor, Hdac5 has been implicated in disease conditions including AKI. Induction of Hdac5 has been reported in cisplatin-induced AKI 63 and septic AKI 64 , which is associated with BMP7 suppression, leading to the inhibition of tubular cell proliferation and repair. Future investigation should extend to these genes to have a comprehensive understanding of DNA methylation in AKI.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Guo

Pei

Xiao

et al. 2017

Kidney International

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DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic and coding DNA sequences, some were located in the promoter or promoter regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of DNA methylation inhibitor 5-Aza-2′-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

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Section: Discussionmentioning

confidence: 99%

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Guo

Pei

Xiao

et al. 2017

Kidney International

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“…Considering that SIRT1 is an important nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase which regulates stress responses, inflammation, apoptosis and cellular senescence, and plays an important role in the development of several renal diseases474849505152, we investigated its expression in rat renal tissue after severe burns. It was showed that the level of SIRT1 was decreased after burns and recovered after the administration of melatonin.…”

Section: Discussionmentioning

confidence: 99%

“…SIRT1 plays an important role in the development of several renal diseases474849505152, and its activation reduces the occurrence of AKI induced by drugs, toxicants and ischemic-reperfusion injury. In mouse proximal tubular epithelial cell model, the administration of cis-platinum leads to the inhibition of SIRT1 as well as ac-p53, PUMA-α, Bax and cleaved-caspase-3, while resveratrol can reverse the effects47.…”

Section: Discussionmentioning

confidence: 99%

Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

Bai

Gao

et al. 2016

Sci Rep

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Acute kidney injury (AKI) is a common complication after severe burns. Melatonin has been reported to protect against multiple organ injuries by increasing the expression of SIRT1, a silent information regulator that regulates stress responses, inflammation, cellular senescence and apoptosis. This study aimed to investigate the protective effects of melatonin on renal tissues of burned rats and the role of SIRT1 involving the effects. Rat severely burned model was established, with or without the administration of melatonin and SIRT1 inhibitor. The renal function and histological manifestations were determined to evaluate the severity of kidney injury. The levels of acetylated-p53 (Ac-p53), acetylated-p65 (Ac-p65), NF-κB, acetylated-forkhead box O1 (Ac-FoxO1), Bcl-2 and Bax were analyzed to study the underlying mechanisms. Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling.

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“…Molecular evidence has indicated that expression of SIRT1 is able to decrease the acetylation of NF-κB and reduce the toxic effect of cisplatin on kidney tubules. Additionally, a previous study indicated that abnormal activation of NF-κB may promote inflammatory responses and autoimmune responses, which results in the expansion of the extracellular matrix, inflammatory cell infiltration and renal tubule interstitial fibrosis (33).…”

Section: Discussionmentioning

confidence: 99%

Tangshen formula improves inflammation in renal tissue of diabetic nephropathy through SIRT1/NF-κB pathway

Zhang

Gao

et al. 2017

Exp Ther Med

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Abstract. The present study investigated the mechanism underlying the anti-inflammatory effects of Tangshen formula (TS) in Sprague Dawley (SD) rats with diabetic nephropathy (DN). A rat model of DN was established by intraperitoneal injection of 1% (40 mg/kg) streptozotocin and administration of a high fat and glucose diet. Subsequently, SD rats were randomly divided into six groups (n=8): A DN group, a valsartan group, a high-dose TS group, a middle-dose TS group, a low-dose TS group and a control group with normal SD rats. Once rats received their allocated treatment for 12 weeks, body weight and kidney weight were recorded, and fasting blood glucose, ratio of urinary protein, β 2 -MG and creatinine clearance rate were determined. Furthermore, hemodynamic indices, including plasma viscosity and whole blood reduction viscosity were detected. Immunohistochemistry was used to detect the infiltration of macrophages in the kidneys of rats. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to investigate the activation; mRNA and protein expression levels of monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor (MIF), nuclear factor-κB (NF-κB) and sirtuin-1 (SIRT1) in each group. In comparison with the DN group, each biochemical indicator of rats in the high-dose TS group was significantly decreased (P<0.05). Blood viscosity in each treatment group was significantly decreased when compared with the DN group (P<0.01). Hematoxylin and eosin staining indicated that the infiltration of macrophages was significantly decreased in the high-dose TS group when compared with the DN group (P<0.01). mRNA and protein expression levels of MCP-1 and MIF in the high-dose TS group were significantly decreased when compared with the DN group (P<0.05). In the treatment groups, SITR1 mRNA expression levels were significantly increased, whereas the mRNA expression levels of NF-κB were significantly decreased (P<0.01). Western blotting results indicated a significant decrease in the protein expression levels of acetylated NF-κB in the treatment groups when compared with the DN group (P<0.01) and the propensity of protein expression of the other inflammatory factors were consistent with the mRNA findings. The results of the high-dose TS group were similar to those of the valsartan group. The present study indicates that TS was able to activate SITR1, which lead to NF-κB deacetylation, thus reducing the release of inflammatory factors and decreasing the severity of diabetic nephropathy.

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Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney

Cited by 21 publications

References 32 publications

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

Tangshen formula improves inflammation in renal tissue of diabetic nephropathy through SIRT1/NF-κB pathway

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