Effect of echinacoside on kidney fibrosis by inhibition of TGF-&amp;beta;1/Smads signaling pathway in the db/db mice model of diabetic nephropathy

Tang, Feng; Hao, Yarong; Zhang, Xue; Qin, Jian

doi:10.2147/dddt.s143805

Cited by 63 publications

(51 citation statements)

References 30 publications

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“…ROS is associated with EMT induced by TGF-β1, aldosterone, albumin or oxidized low-density lipoprotein, which is consistent with earlier studies (39). The upregulation of TGF-β1 in vitro and in vivo serves a significant role in the pathogenesis of DN (15,40) and it was demonstrated that TGF-β1 expression was increased under HG conditions. H 2 O 2 , which was used as an agent to simulate oxidative stress, also increased the expression of TGF-β1.…”

Section: Gsh (Mg/g Protein) T-sod (U/mg Protein) Mda (µMol/g Protein)supporting

confidence: 88%

ROS induces epithelial‑mesenchymal transition via the TGF‑β1/PI3K/Akt/mTOR pathway in diabetic nephropathy

et al. 2018

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Oxidative stress has been reported to serve an important role in the development and progression of diabetic nephropathy (DN). Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells promotes renal fibrosis in DN, while the mechanism of reactive oxygen species (ROS)-mediated EMT is not fully understood. The aim of the present study was to investigate the effect of high glucose-induced ROS on the activation of the transforming growth factor (TGF)-β1/phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in a normal rat kidney tubular epithelial cell line (NRK-52E) and rats with type 1 diabetes. In vitro, high glucose-stimulated ROS production resulted in increased TGF-β1 expression as well as an increase in the Akt and mTOR phosphorylation ratio, resulting in EMT. When cells were pre-treated with ROS inhibitors, changes in TGF-β1, Akt and mTOR were significantly ameliorated. In vivo, diabetic rats experienced a significant decline in renal function and severe renal fibrosis compared with control rats at 8 weeks following streptozocin injection. Levels of malondialdehyde and TGF-β1/PI3K/Akt/mTOR pathway activation were increased in the renal cortex of rats with diabetes compared with the control rats. Furthermore, renal fibrosis was further aggravated in DN compared with the control rats. The results of the present study suggest that ROS serves an important role in mediating high glucose-induced EMT and inhibits activation of the TGF-β1/PI3K/Akt/mTOR pathway. ROS may therefore have potential as a treatment approach to prevent renal fibrosis in DN.

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Section: Gsh (Mg/g Protein) T-sod (U/mg Protein) Mda (µMol/g Protein)supporting

confidence: 88%

ROS induces epithelial‑mesenchymal transition via the TGF‑β1/PI3K/Akt/mTOR pathway in diabetic nephropathy

et al. 2018

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“…), as well as renal tubular basement membrane thickening and tubular atrophy (Tang et al . ), respectively. We showed elevated UTX in all three major renal cell types involved in DKD, implicating a critical role of UTX in DKD.…”

Section: Discussionmentioning

confidence: 95%

“…1). Mesangial cells, podocytes and tubular cells are all involved in the development of DKD, which are responsible for mesangial expansion and accumulation of extracellular matrix (Gruden et al 2005), podocyte loss, podocyte foot processes fusion and effacement (Maezawa et al 2015), as well as renal tubular basement membrane thickening and tubular atrophy (Tang et al 2017), respectively. We showed elevated UTX in all three major renal cell types involved in DKD, implicating a critical role of UTX in DKD.…”

Section: Discussionmentioning

confidence: 99%

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

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Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

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“…Huiling Wu et al reported that TLR4/NF-κB signaling pathway was activated in DN model in vivo [33]. Fengjuan Tang et al demonstrated that echinacoside was able to inhibit kidney brosis through regulating TGF-β1/Smad signaling pathway [34]. Additionally, Yaning Wang et al reported that astragaloside delayed the process of renal brosis in diabetic mice by in uencing the TGF-β/SMADS signaling pathway and downregulating TGF-β1, SMAD2/3 [35].…”

Section: Discussionmentioning

confidence: 99%

Psoralen alleviates high glucose-induced HK-2 cell injury by inhibition of Smad 2 signaling via upregulation of microRNA 874

Lin¹,

Zhong²,

Li³

et al. 2020

Preprint

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Abstract Background: Diabetic nephropathy (DN) causes the vast proportion of excess mortality for patients with diabetes. Novel therapeutic approaches slowing down its incidence is still lacking. Psoralen is the major active ingredient of Psoralea corylifolia Linn. (PCL), which was used to treat a number of diseases. In this study, we aimed to investigate whether psoralen could alleviate DN using in vitro model. Methods: Cell viability assay and immunofluorescence were used to evaluate the effect of psoralen on high glucose (HG)-stimulated human kidney HK-2 cells (48 h). RT-qPCR was used to detect the expressions of miRNA in cells. Cell transfection, apoptosis assay, inflammatory cytokines detection and Western blot were further performed to explore the underlying molecular mechanisms.Results: HG-induced toxicity of HK-2 cells was alleviated by psoralen. Meanwhile, the secretion of inflammatory cytokines and extracellular matrix (ECM) accumulation induced by HG in HK-2 cells were also decreased by psoralen. In addition, the expression of miR-874 in HK-2 cells was significantly upregulated by psoralen. Western blot assays indicated that psoralen could reverse HG-induced increase of TLR-4/NF-κB and Smad2 via upregulation of miR-874.Conclusion: This study demonstrated that psoralen could significantly alleviate HG-induced HK-2 cell injury via upregulation of miR-874. In addition, HG-induced increase of TLR-4/NF-κB and Smad2 was revered by psoralen. Therefore, psoralen might serve as an agent for the treatment of DN.

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Effect of echinacoside on kidney fibrosis by inhibition of TGF-β1/Smads signaling pathway in the db/db mice model of diabetic nephropathy

Cited by 63 publications

References 30 publications

ROS induces epithelial‑mesenchymal transition via the TGF‑β1/PI3K/Akt/mTOR pathway in diabetic nephropathy

ROS induces epithelial‑mesenchymal transition via the TGF‑β1/PI3K/Akt/mTOR pathway in diabetic nephropathy

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Psoralen alleviates high glucose-induced HK-2 cell injury by inhibition of Smad 2 signaling via upregulation of microRNA 874

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