Anti-fibrotic effect of wogonin in renal tubular epithelial cells via Smad3-dependent mechanisms

Meng, Xiao‐Ming; Ren, Gui-Ling; Gao, Li; Li, Hai-Di; Wang, Weifeng; Li, Xiaofeng; Xu, Tao; Wang, Xuefu; Ma, Tao; Li, Zeng; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun

doi:10.1016/j.ejphar.2016.07.014

Cited by 28 publications

(19 citation statements)

References 38 publications

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“…16 Our study showed an increasing accumulation of ECM in the kidney of diabetic mice and HG-induced mesangial cells, which implied the occurrence of renal fibrosis, while the administration of wogonin retarded the tendency of ongoing fibrosis. This is in consensus with the results provided by Meng et al 25 that wogonin may serve as a potential antifibrotic agent in treating renal fibrosis.…”

Section: Discussionsupporting

confidence: 91%

“…24 Additionally, wogonin can alleviate the fibrosis of renal tubular epithelial cells, and the TGF-β1/Smad pathway may be a potential target. 25 Wogonin inhibits inflammatory factors in acute kidney injury (AKI) models, which indicates that it may play an important role in renal inflammation. 26 The studies of wogonin provide theoretical basis, then diabetic models and HG-induced glomerular mesangial cells were used to explore the effects of Wogonin on DN.…”

Section: Introductionmentioning

confidence: 99%

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<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

Zheng¹,

Zhu²,

Lei³

et al. 2020

DDDT

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Introduction: Diabetic nephropathy (DN) has become an increasing threat to health, and inflammation and fibrosis play important roles in its progression. Wogonin, a flavonoid, has been proven to suppress inflammation and fibrosis in various diseases, including acute kidney injury. This study aimed at investigating the effect of wogonin on diabetes-induced renal inflammation and fibrosis. Materials and Methods: Streptozotocin (STZ)-induced diabetic mouse models received gavage doses of wogonin (10, 20, and 40 mg/kg) for 12 weeks. Metabolic indices from blood and urine and pathological damage of glomerulus in the diabetic model were assessed. Glomerular mesangial cells SV40 were cultured in high glucose (HG) medium containing wogonin at concentrations of 1.5825, 3.125, and 6.25 μg/mL for 24 h. Inflammation and fibrosis indices were evaluated by histopathological, Western blotting, and PCR analyses. Results: Wogonin treatment ameliorated albuminuria and histopathological lesions in diabetic mice. Inflammatory cytokines, such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and related signaling pathway NF-κB were downregulated after the administration of wogonin in vivo and in vitro. Furthermore, wogonin reduced the expression of extracellular matrix (ECM), including fibronectin (FN), collagen IV (Col-IV), α-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1) in the kidneys of diabetic mice and HG-induced mesangial cells. Moreover, the inhibition of TGF-β1/Smad3 pathway might be responsible for these changes. Conclusion: Wogonin may ameliorate renal inflammation and fibrosis in diabetic nephropathy by inhibiting the NF-κB and TGF-β1/Smad3 signaling pathways.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

Zheng¹,

Zhu²,

Lei³

et al. 2020

DDDT

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“…Baicalein remarkably improved renal dysfunction, ameliorated kidney fibrosis and alleviated EMT and oxidative stress in hyperuricemia mice [100]. Wogonin and wogonoside effectively blocked the TGF-β1-triggered fibrotic response both in vitro and in vivo by exerting inhibitory effects on TGF-β/Smad3 signaling, indicating wogonin may be utilized as a potential anti-fibrotic effects [101]. Scutellaria barbata (SB) is a promising medicinal natural product.…”

Section: Targeting Tgf-β1/smad Signaling By Isolated Compoundsmentioning

confidence: 99%

New insights into TGF-β/Smad signaling in tissue fibrosis

Chen

Wang

et al. 2018

Chemico-Biological Interactions

794

480

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Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. This review presents an overview of the molecular mechanisms of TGF-β/Smad signaling pathway in renal, hepatic, pulmonary and cardiac fibrosis, followed by an in-depth discussion of their molecular mechanisms of intervention effects both in vitro and in vivo. The role of TGF-β/Smad signaling pathway in tumor or cancer is also discussed. Additionally, the current advances also highlight targeting TGF-β/Smad signaling pathway for the prevention of tissue fibrosis. The review reveals comprehensive pathophysiological mechanisms of tissue fibrosis. Particular challenges are presented and placed within the context of future applications against tissue fibrosis.

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“…Western blotting analysis was performed as described previously. 18,19 Then membranes were blocked with 5% milk for 2 h in order to break nonspecific binding. Subsequently, membranes were incubated with the primary antibody against KIM-1, β-actin, Nox2, Nox4, RIPK1, RIPK3, Phosphor-MLKL and cleaved-caspase3 overnight at 4°C, followed by incubation with secondary antibody at room temperature for 2 h. Signals were captured with LiCor/Odyssey infrared image system (LI-COR Biosciences, Lincoln, NE, USA).…”

Section: Western Blotting Analysismentioning

confidence: 99%

NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation

Meng

Ren

Gao

et al. 2018

Laboratory Investigation

Self Cite

158

117

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The goal of this study was to elucidate the functional role of Nox4 during acute kidney injury (AKI). NADPH oxidases are a major source of reactive oxygen species (ROS) in the kidney in normal and pathological conditions. Among NADPH oxidase isoforms, NADPH oxidase4 (Nox4) is highly expressed in the kidney and has an important role in kidney diseases, such as diabetic nephropathy and renal carcinoma. We previously found that Nox4 expression significantly increased in the toxic AKI model. However, its functional role and mechanism of action in AKI are still unknown. We scavenged ROS with apocynin in vitro and in vivo and found it attenuated cisplatin-triggered renal function decline. It also alleviated programmed cell death and renal inflammation, indicating a critical role for ROS in mediating AKI. Nox4 protein and mRNA levels were substantially upregulated by cisplatin in vivo and in vitro. Nox4 knockdown alleviated cisplatin-induced cell death and inflammatory response, while Nox4 overexpression aggravated them. Moreover, N-acetyl-L-cysteine (NAC)-mediated inhibition of ROS suppressed cell injury led by Nox4 overexpression, indicating Nox4-mediated ROS generation may be the key mediator in cisplatin-induced nephrotoxicity. Mechanistically, excessive expression of Nox4 induced programmed cell death, especially RIP-mediated necroptosis. Finally, we tested whether Nox4 is a potential therapeutic target using an AKI mouse model by injecting a lentivirus-packaged Nox4 shRNA plasmid through tail vein. Disruption of Nox4 led to renal function recovery, kidney damage relief and reduced inflammation. We conclude that Nox4 aggravates cisplatin-induced nephrotoxicity by promoting ROS-mediated programmed cell death and inflammation. Thus Nox4 may serve as a potential therapeutic target in the treatment of AKI.

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Anti-fibrotic effect of wogonin in renal tubular epithelial cells via Smad3-dependent mechanisms

Cited by 28 publications

References 38 publications

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

New insights into TGF-β/Smad signaling in tissue fibrosis

NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation

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