Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction

Tikoo, Kulbhushan; Sharma, Ekta; Amara, Venkateswara Rao; Pamulapati, Himani; Dhawale, Vaibhav

doi:10.1074/jbc.c116.732990

Cited by 35 publications

(23 citation statements)

References 40 publications

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“…It provides new evidence that MET is a promising drug for prevention and/or treatment of PE. MET was reported to decrease blood pressure and improve renal dysfunction in experimental rats and patients [24,25], and our study showed that MET was also effective in LPS-induced PE-like rats. In addition, PE can restrict fetal growth, and FGR often complicates PE pregnancies [26].…”

Section: Met Inhibited Lps-induced Nf-jb Activation In Placentassupporting

confidence: 62%

Protective effect of metformin on a rat model of lipopolysaccharide‐induced preeclampsia

Zhang

Zhu

2019

Fundamemntal Clinical Pharma

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Recent in vitro and clinical studies have found that metformin (MET) may play a preventive or therapeutic role in preeclampsia (PE) and may be a candidate drug for the prevention and/or treatment of PE. In this study, we used lipopolysaccharide (LPS) to induce a PE‐like rat model and investigated the intervention effect of MET from the perspectives of clinical manifestations, placental morphology, serum marker for placental injury, systemic inflammatory response and oxidative/nitrative stress, and placental nuclear factor‐κB (NF‐κB) signaling. The results showed that MET improved LPS‐induced hypertension, proteinuria, fetal growth restriction (FGR) and stillbirth, alleviated placental injury and decreased maternal serum marker alpha‐fetoprotein (MS‐AFP) level; MET suppressed LPS‐induced TNF‐α and IL‐6 productions, reduced oxidative/nitrative stress as evidenced by increased superoxide dismutase (SOD) activity, decreased inducible nitric oxide synthase (iNOS) activity, and decreased levels of malondialdehyde (MDA) and nitric oxide (NO); MET inhibited LPS‐induced NF‐κB activation in placentas. Based on these findings, it can be concluded that MET is beneficial to the PE‐like rat model by protecting placentas from injury, suppressing systemic inflammatory response and oxidative/nitrative stress, and inhibiting placental NF‐κB signaling pathway. MET is a promising drug for prevention and/or treatment of PE.

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Section: Met Inhibited Lps-induced Nf-jb Activation In Placentassupporting

confidence: 62%

Protective effect of metformin on a rat model of lipopolysaccharide‐induced preeclampsia

Zhang

Zhu

2019

Fundamemntal Clinical Pharma

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“…The unforeseen capacity of biguanides to directly inhibit the demethylation activity of KDM6A/UTX might provide mechanistic support for recent studies showing that metformin efficiently prevents fatty acid/high‐fat diet‐induced metabolic memory (Tikoo, Sharma, Amara, Pamulapati & Dhawale, 2016), which is epigenetically driven by decreased abundance of H3K27me3 on the FOXO1 promoter (Kumar, Pamulapati & Tikoo, 2016), as well as the synergistic interactions between metformin and the KDM6 inhibitor GSK‐J4 in a panel of non‐small cell lung carcinoma cell lines (Watarai et al., 2016). However, one might argue that the in silico capacity of metformin to bind the catalytic site of KDM6A/UTX occurs with rather high binding energies, whereas metformin‐driven reduction in KDM6A/UTX enzymatic activity in vitro and global augmentation of the H3K27me3 mark in cellulo were obtained by applying high, nonphysiological millimolar concentrations in excess of the therapeutic levels achieved in human patients.…”

Section: Discussionmentioning

confidence: 78%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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“…Therefore we focused on the tubular epithelial cells to investigate the role of HDAC11 hereafter. Angiotensin II (Ang II) has been reported to play a key role promoting renal fibrosis in model animals (Chevalier, 2006;Pandey et al, 2016;Tikoo et al, 2016;Xu et al, 2017). Next, cultured human renal tubular epithelial cells (HK-2) were treated with Ang II.…”

Section: Hdac11 Is Up-regulated By Pro-fibrogenic Stimuli In Vivo Andmentioning

confidence: 99%

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

Mao

Liu

Zhang

et al. 2020

Front. Cell Dev. Biol.

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Renal fibrosis represents a key pathophysiological process in patients with chronic kidney diseases (CKD) and is typically associated with a poor prognosis. Renal tubular epithelial cells (RTECs), in response to a host of pro-fibrogenic stimuli, can trans-differentiate into myofibroblast-like cells and produce extracellular matrix proteins to promote renal fibrosis. In the present study we investigated the role of histone deacetylase 11 (HDAC11) in this process and the underlying mechanism. We report that expression levels of HDAC11 were up-regulated in the kidneys in several different animal models of renal fibrosis. HDAC11 was also up-regulated by treatment of Angiotensin II (Ang II) in cultured RTECs. Consistently, pharmaceutical inhibition with a smallmolecule inhibitor of HDAC11 (quisinostat) attenuated unilateral ureteral obstruction (UUO) induced renal fibrosis in mice. Similarly, HDAC11 inhibition by quisinostat or HDAC11 depletion by siRNA blocked Ang II induced pro-fibrogenic response in cultured RTECs. Mechanistically, HDAC11 interacted with activator protein 2 (AP-2α) to repress the transcription of Kruppel-like factor 15 (KLF15). In accordance, KLF15 knockdown antagonized the effect of HDAC11 inhibition or depletion and enabled Ang II to promote fibrogenesis in RTECs. Therefore, we data unveil a novel AP-2α-HDAC11-KLF15 axis that contributes to renal fibrosis.

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Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction

Cited by 35 publications

References 40 publications

Protective effect of metformin on a rat model of lipopolysaccharide‐induced preeclampsia

Protective effect of metformin on a rat model of lipopolysaccharide‐induced preeclampsia

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

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