Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat

Luo, Weigang; Yu, Yijin; Wang, Hao; Liu, Kun; Wang, Yu; Huang, Minling; Xuan, Chenhao; Li, Yanning; Qi, Jinsheng

doi:10.1007/s00592-020-01552-2

Cited by 24 publications

(21 citation statements)

References 40 publications

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“…Even in diabetes, the administration of BHB is reported to alleviate retinopathy and nephropathy [41,42]. Based on our serial investigations [22,23], this study found that BHB could promote claudin-5 generation and antagonise diabetes-associated cardiac microvascular hyperpermeability in vivo and in vitro. Clinical studies have proved that oral administration of BHB has beneficial effects for participants, indicating its potential clinical application [43][44][45].…”

Section: Discussionmentioning

confidence: 75%

“…The former four DM groups were injected intraperitoneally with streptozotocin (STZ; 40 mg/kg, dissolved in freshly made 0.1 mol/l citrate buffer, pH 4.4, 10 mg/ml) to induce diabetes, as previously reported [27]. Rats in the BHB1, BHB2 and BHB3 groups were injected subcutaneously with 1 6 0 m g k g − 1 d a y − 1 , 2 0 0 m g k g − 1 d a y − 1 a n d 240 mg kg −1 day −1 BHB (Sigma, Steinheim, Germany), respectively [22,23]; rats in the DM and Con groups were administered an equivalent volume of saline (154 mmol/l NaCl). Fasting blood glucose and body weight were measured at 3 days and 10 weeks after diabetes induction.…”

Section: Methodsmentioning

confidence: 99%

“…Besides supplying energy, BHB has various cardiovascular protective effects that are especially strong in endothelial cells [19][20][21]. We have published a series of studies in rat models of diabetes, demonstrating that BHB treatment elevated the expression of vascular endothelial growth factor to alleviate aortic endothelial injury, and promoted the generation of matrix metalloproteinase-2 to antagonise glomerulosclerosis [22,23]. A broad spectrum of targets has been proposed for the protective effects of BHB [18].…”

Section: Introductionmentioning

confidence: 99%

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β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes

et al. 2020

Diabetologia

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Aims/hypothesis Microvascular endothelial hyperpermeability, mainly caused by claudin-5 deficiency, is the initial pathological change that occurs in diabetes-associated cardiovascular disease. The ketone body β-hydroxybutyrate (BHB) exerts unique beneficial effects on the cardiovascular system, but the involvement of BHB in promoting the generation of claudin-5 to attenuate cardiac microvascular hyperpermeability in diabetes is poorly understood. Methods The effects of BHB on cardiac microvascular endothelial hyperpermeability and claudin-5 generation were evaluated in rats with streptozotocin-induced diabetes and in high glucose (HG)-stimulated human cardiac microvascular endothelial cells (HCMECs). To explore the underlying mechanisms, we also measured β-catenin nuclear translocation, binding of β-catenin, histone deacetylase (HDAC)1, HDAC3 and p300 to the Claudin-5 (also known as CLDN5) promoter, interaction between HDAC3 and β-catenin, and histone acetylation in the Claudin-5 promoter. Results We found that 10 weeks of BHB treatment promoted claudin-5 generation and antagonised cardiac microvascular endothelial hyperpermeability in rat models of diabetes. Meanwhile, BHB promoted claudin-5 generation and inhibited paracellular permeability in HG-stimulated HCMECs. Specifically, BHB (2 mmol/l) inhibited HG-induced HDAC3 from binding to the Claudin-5 promoter, although nuclear translocation or promoter binding of β-catenin did not change with BHB treatment. In addition, BHB prevented the binding and co-localisation of HDAC3 to β-catenin in HG-stimulated HCMECs. Furthermore, using mass spectrometry, acetylated H3K14 (H3K14ac) in the Claudin-5 promoter following BHB treatment was identified, regardless of whether cells were stimulated by HG or not. Although reduced levels of acetylated H3K9 in the Claudin-5 promoter were found following HG stimulation, increased H3K14ac was specifically associated with BHB treatment. Conclusions/interpretation BHB inhibited HDAC3 and caused acetylation of H3K14 in the Claudin-5 promoter, thereby promoting claudin-5 generation and antagonising diabetes-associated cardiac microvascular hyperpermeability.

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Section: Discussionmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes

et al. 2020

Diabetologia

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“…Acetylation of histone H3K9 (H3K9ac) is involved in the pathogenesis of obesity in ob/ob mice and diabetes heart disease in db/db mice [ 24 ]. Recently, histone H3K9 β -hydroxybutyrylation (H3K9bhb) upregulates matrix metalloproteinase-2 (MMP-2) to antagonize glomerulosclerosis in diabetic rat [ 25 ]; H3K9bhb ameliorates aortic endothelial injury by promoting the generation of vascular endothelial growth factor (VEGF) in diabetic rats [ 26 ]. The above studies suggest that histone Kac, Kbhb, and Kbu may coexist or cross-talk at the H3K9 site, which may have synergistic or antagonistic effects on related gene expression.…”

Section: Discussionmentioning

confidence: 99%

Sodium Butyrate Attenuates Diabetic Kidney Disease Partially via Histone Butyrylation Modification

Zhou

Cheng

et al. 2022

Mediators of Inflammation

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Inflammation and fibrosis are the important pathophysiologic processes in diabetic kidney disease (DKD), which is induced by epigenetics, especially histone posttranslational modification (HPTMs). Recent reports highlighted that butyrate, one of the short-chain fatty acids (SCFAs) primarily originated from the fermentation of dietary fiber in the gut, attenuates inflammation and fibrosis in the prevention and treatment of DKD; however, the molecular mechanisms are still unclear. Histone lysine butyrylation (Kbu), a novel histone modification marker induced by butyrate, has been found to be involved in the regulation of pathophysiological processes. To reveal the mechanisms of butyrate-induced histone (Kbu), in the prevention and treatment of DKD, both DKD models in vivo and in vitro were treated with sodium butyrate (NaB). Our results confirmed that exogenous NaB improved the disorder of glucose and lipid metabolism, prevented proteinuria and renal failure, and inhibited renal inflammation and fibrosis. Meanwhile, NaB also induced histone Kbu and H3K9 butyrylation (H3K9bu) in vivo and in vitro; however, inhibition of histone Kbu with the histone modification enzyme p300 inhibitor A485 reversed the anti-inflammatory and anti-fibrosis effects of NaB. In conclusion, our data reveal that NaB antagonizes renal inflammatory and fibrosis injury and attenuates DKD possibly via histone Kbu, suggesting that butyrate-induced histone Kbu or H3K9bu may be an important molecular mechanism in the pathogenesis and treatment of DKD.

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“…In obese diabetic mice treated with dapagliflozin, a selective competitive inhibitor of sodium/glucose cotransporter 2 (SGLT2), elevated β-hydroxybutyric acid levels mediated Kbhb of H3K9 to promote the expression of the adiponectin gene in adipocytes, partially accounting for the molecular mechanisms by which SGLT2 inhibitors protect against cardiovascular events in diabetic patients [ 198 ]. BHB-induced Kbhb of H3K9 can antagonize glomerulosclerosis induced by diabetes and alleviate depressive behaviours by modulating specific gene expression through promoters [ 68 , 69 ].…”

Section: Introductionmentioning

confidence: 99%

Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification

et al. 2022

J Exp Clin Cancer Res

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Metabolites are intermediate products of cellular metabolism catalysed by various enzymes. Metabolic remodelling, as a biochemical fingerprint of cancer cells, causes abnormal metabolite accumulation. These metabolites mainly generate energy or serve as signal transduction mediators via noncovalent interactions. After the development of highly sensitive mass spectrometry technology, various metabolites were shown to covalently modify proteins via forms of lysine acylation, including lysine acetylation, crotonylation, lactylation, succinylation, propionylation, butyrylation, malonylation, glutarylation, 2-hydroxyisobutyrylation and β-hydroxybutyrylation. These modifications can regulate gene expression and intracellular signalling pathways, highlighting the extensive roles of metabolites. Lysine acetylation is not discussed in detail in this review since it has been broadly investigated. We focus on the nine aforementioned novel lysine acylations beyond acetylation, which can be classified into two categories: histone acylations and nonhistone acylations. We summarize the characteristics and common functions of these acylation types and, most importantly, provide a glimpse into their fine-tuned control of tumorigenesis and potential value in tumour diagnosis, monitoring and therapy.

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Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat

Cited by 24 publications

References 40 publications

β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes

β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes

Sodium Butyrate Attenuates Diabetic Kidney Disease Partially via Histone Butyrylation Modification

Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification

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