Wen-Shen-Jian-Pi-Hua-Tan decoction protects against early obesity-related glomerulopathy by improving renal bile acid composition and suppressing lipogenesis, inflammation, and fibrosis,Phytomedicine

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Wen-Shen-Jian-Pi-Hua-Tan decoction protects against early obesity-related glomerulopathy by improving renal bile acid composition and suppressing lipogenesis, inflammation, and fibrosis
Phytomedicine ( IF 6.7 ) Pub Date : 2023-05-04 , DOI: 10.1016/j.phymed.2023.154861
Daofei Song ₁ , Aijie Zhang ₂ , Xu Hu ₃ , MingXing Zeng ₃ , Huimin Zhou ₃

Affiliation

Background

Obesity is an independent predictor of chronic kidney disease (CKD) development and may directly lead to kidney lesions such as obesity-related glomerulopathy (ORG) which might play a vital pathogenic role in obese patients with CKD. Wen-Shen-Jian-Pi-Hua-Tan decoction (WSHT) has been clinically used for the treatment of obesity and obesity-related metabolic diseases for years. However, the renoprotective effects and potential mechanism of action of WSHT against ORG remain unknown.

Purpose

This study aimed to explore the potential effect of WSHT on ORG and reveal its mechanisms in high-fat diet (HFD)-induced obese rats.

Methods

An animal model of early stage ORG was established using HFD-induced obese rats. After treatment with WSHT for 6 weeks, an integrated metabolomics and molecular biology strategy was utilized to illustrate the effects and mechanism of WSHT on ORG. First, UPLC-ESI-MS/MS-based targeted metabolomics was used to analyze renal bile acid (BA) levels. Biochemical, histological, and immunofluorescence assays; electron microscopy; and western blotting were performed to evaluate the efficacy of WSHT against ORG and its underlying mechanisms in vivo.

Results

Our results showed that an HFD led to hyperlipidemia, proteinuria, renal lipid deposition, effacement of podocyte foot processes, and increased expression of proinflammatory factors and profibrotic growth factors in ORG rats. In addition, an HFD decreased the levels of renal BAs such as cholic acid, chenodeoxycholic acid, and lithocholic acid. After 6 weeks of treatment, WSHT markedly attenuated dyslipidemia and reduced body, kidney and epididymal fat weights in ORG rats. WSHT also significantly increased BA levels, suggesting that it altered BA composition; the effects of BAs are closely associated with farnesoid X receptor (FXR) activation. WSHT alleviated fat accumulation, podocyte loss and proteinuria, and reduced the expression of proinflammatory cytokines and profibrotic growth factors in the kidneys of ORG rats. Finally, WSHT remarkably upregulated the renal expression of FXR and salt-induced kinase 1 and blocked the renal expression of sterol regulatory element–binding protein-1c and its target genes.

Conclusion

WSHT attenuated early renal lesions in ORG rats by improving renal BA composition and suppressing lipogenesis, inflammation and fibrosis. This study develops a new way to alleviate obesity-induced renal damages.

中文翻译：

温肾健皮化痰汤通过改善肾胆汁酸组成和抑制脂肪生成、炎症和纤维化来预防早期肥胖相关的肾小球病

背景

肥胖是慢性肾脏病（CKD）发展的独立预测因子，可能直接导致肾脏病变，如肥胖相关性肾小球病（ORG），这可能在肥胖的 CKD 患者中起重要的致病作用。Wen-Shen-Jian-Pi-Hua-Tan deoction (WSHT) 已在临床上用于治疗肥胖和与肥胖相关的代谢性疾病多年。然而，WSHT 对 ORG 的肾脏保护作用和潜在作用机制仍然未知。

目的

本研究旨在探讨 WSHT 对 ORG 的潜在影响，并揭示其在高脂肪饮食 (HFD) 诱导的肥胖大鼠中的作用机制。

方法

使用 HFD 诱导的肥胖大鼠建立早期 ORG 动物模型。用 WSHT 治疗 6 周后，利用综合代谢组学和分子生物学策略来说明 WSHT 对 ORG 的影响和机制。首先，使用基于 UPLC-ESI-MS/MS 的靶向代谢组学分析肾胆汁酸 (BA) 水平。生化、组织学和免疫荧光分析；电子显微镜; 并进行了蛋白质印迹以评估 WSHT 对 ORG 的疗效及其在体内的潜在机制。

结果

我们的研究结果表明，HFD 导致 ORG 大鼠高脂血症、蛋白尿、肾脂质沉积、足细胞足突消失以及促炎因子和促纤维化生长因子的表达增加。此外，HFD 降低了肾 BA 的水平，例如胆酸、鹅去氧胆酸和石胆酸。治疗 6 周后，WSHT 显着减轻了 ORG 大鼠的血脂异常并减少了身体、肾脏和附睾脂肪的重量。WSHT 还显着增加了 BA 水平，表明它改变了 BA 的组成；BA 的作用与法尼醇 X 受体 (FXR) 激活密切相关。WSHT 减轻了脂肪堆积、足细胞丢失和蛋白尿，并降低了 ORG 大鼠肾脏中促炎细胞因子和促纤维化生长因子的表达。最后，