奥利多宁通过抑制Wnt/β-catenin信号通路改善糖尿病肾病的肾脏纤维化。

IF 3 3区 医学 Q1 UROLOGY & NEPHROLOGY Renal Failure Pub Date : 2024-12-01 Epub Date: 2024-06-04 DOI:10.1080/0886022X.2024.2347462
Jushuang Li, Lan Shu, Qianqian Jiang, Baohong Feng, Zhimin Bi, Geli Zhu, Yanxia Zhang, Xiangyou Li, Jun Wu
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引用次数: 0

摘要

糖尿病肾病(DN)是糖尿病患者最严重、最常见的并发症之一,目前在全球范围内占终末期肾病病例的绝大多数。肾小管间质纤维化是导致糖尿病肾病发生和发展的关键因素。Oridonin(Ori)是从红豆杉中提取的一种二萜类化合物,具有多种药理特性。我们之前的研究表明,Ori 可以通过降低炎症反应来预防 DN。然而,Ori 能否减轻 DN 的肾脏纤维化仍是未知数。在此,我们研究了Ori影响糖尿病大鼠和暴露于高葡萄糖(HG)水平的人类近端肾小管上皮细胞(HK-2)的Wnt/β-catenin信号通路的机制。我们的研究结果表明,Ori治疗能显著降低糖尿病大鼠的尿蛋白排泄水平,改善肾功能,减轻肾脏纤维化。在体外,HG 处理增加了 HK-2 细胞的迁移,同时降低了其存活率和增殖率,而 Ori 处理则逆转了这些变化。此外,敲除β-catenin可阻止细胞迁移,并降低Wnt/β-catenin信号相关分子(Wnt4、p-GSK3β和β-catenin)和纤维化相关分子(α-平滑肌肌动蛋白、胶原蛋白I和纤连蛋白)的表达水平。此外,与单独处理相比,Ori处理和β-catenin下调联合使用能产生更明显的生物学效应。这些发现可能提供了第一线证据,表明Ori通过抑制Wnt/β-catenin信号通路缓解了DN的纤维化,从而揭示了治疗肾小管间质纤维化的新途径。
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Oridonin ameliorates renal fibrosis in diabetic nephropathy by inhibiting the Wnt/β-catenin signaling pathway.

Diabetic nephropathy (DN) is one of the most serious and frequent complications among diabetes patients and presently constitutes vast the cases of end-stage renal disease worldwide. Tubulointerstitial fibrosis is a crucial factor related to the occurrence and progression of DN. Oridonin (Ori) is a diterpenoid derived from rubescens that has diverse pharmacological properties. Our previous study showed that Ori can protect against DN by decreasing the inflammatory response. However, whether Ori can alleviate renal fibrosis in DN remains unknown. Here, we investigated the mechanism through which Ori affects the Wnt/β-catenin signaling pathway in diabetic rats and human proximal tubular epithelial cells (HK-2) exposed to high glucose (HG) levels. Our results revealed that Ori treatment markedly decreased urinary protein excretion levels, improved renal function and alleviated renal fibrosis in diabetic rats. In vitro, HG treatment increased the migration of HK-2 cells while reducing their viability and proliferation rate, and treatment with Ori reversed these changes. Additionally, the knockdown of β-catenin arrested cell migration and reduced the expression levels of Wnt/β-catenin signaling-related molecules (Wnt4, p-GSK3β and β-catenin) and fibrosis-related molecules (α-smooth muscle actin, collagen I and fibronectin), and Ori treatment exerted an effect similar to that observed after the knockdown of β-catenin. Furthermore, the combination of Ori treatment and β-catenin downregulation exerted more pronounced biological effects than treatment alone. These findings may provide the first line of evidence showing that Ori alleviates fibrosis in DN by inhibiting the Wnt/β-catenin signaling pathway and thereby reveal a novel therapeutic avenue for treating tubulointerstitial fibrosis.

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来源期刊
Renal Failure
Renal Failure 医学-泌尿学与肾脏学
CiteScore
3.90
自引率
13.30%
发文量
374
审稿时长
1 months
期刊介绍: Renal Failure primarily concentrates on acute renal injury and its consequence, but also addresses advances in the fields of chronic renal failure, hypertension, and renal transplantation. Bringing together both clinical and experimental aspects of renal failure, this publication presents timely, practical information on pathology and pathophysiology of acute renal failure; nephrotoxicity of drugs and other substances; prevention, treatment, and therapy of renal failure; renal failure in association with transplantation, hypertension, and diabetes mellitus.
期刊最新文献
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