Empagliflozin 通过调节肠道-肾脏轴对高脂饮食诱发肥胖相关性肾小球病变的雷诺保护作用

IF 5 2区 生物学 Q2 CELL BIOLOGY American journal of physiology. Cell physiology Pub Date : 2024-10-01 Epub Date: 2024-08-26 DOI:10.1152/ajpcell.00367.2024
Lei Lei, Ting Zhu, Tian-Jiao Cui, Yvonne Liu, Johann-Georg Hocher, Xin Chen, Xue-Mei Zhang, Kai-Wen Cai, Zi-Yan Deng, Xiao-Hua Wang, Chun Tang, Lian Lin, Christoph Reichetzeder, Zhi-Hua Zheng, Berthold Hocher, Yong-Ping Lu
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引用次数: 0

摘要

背景:肥胖相关肾小球病(ORG)的发病率不断上升,对公众健康构成了严重威胁。钠-葡萄糖共转运体-2(SGLT2)抑制剂能有效降低肥胖者的体重和总脂肪量,并阻止肥胖相关性肾小球肾病的发展。然而,它们对 ORG 起保护作用的内在机制仍不清楚:我们利用 C57BL/6J 小鼠建立了高脂饮食诱导的 ORG 模型,并将其分为三组:正常饲料组(NCD 组)、使用安慰剂治疗的高脂饮食组(ORG 组)和使用恩格列净治疗的高脂饮食组(EMPA 组)。我们对粪便进行了 16S 核糖体 RNA 基因测序,并分析了肾脏、粪便、肝脏和血清样本中的代谢物:结果:与 NCD 小鼠相比,ORG 小鼠的尿白蛋白肌酐比值、胆固醇、甘油三酯水平和肾小球直径均有所增加(所有 P < 0.05)。EMPA治疗可明显缓解这些参数(所有P < 0.05)。多组织代谢组学分析显示,ORG小鼠的脂质代谢重编程在EMPA治疗后发生了明显改变。MetOrigin分析表明,EMPA相关的脂质代谢途径与肠道微生物群的改变密切相关,其特征是固氮菌和脱硫弧菌的丰度降低,而Akkermansia的丰度增加(所有P < 0.05):结论:ORG小鼠的代谢平衡,尤其是脂质代谢平衡受到破坏,并与肠道微生物群的改变密切相关,从而导致了ORG的进展。EMPA治疗通过肠道-肾脏轴调节脂质代谢,改善了肾脏功能和形态,是治疗ORG的一种新方法。
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Renoprotective effects of empagliflozin in high-fat diet-induced obesity-related glomerulopathy by regulation of gut-kidney axis.

The increasing prevalence of obesity-related glomerulopathy (ORG) poses a significant threat to public health. Sodium-glucose cotransporter-2 (SGLT2) inhibitors effectively reduce body weight and total fat mass in individuals with obesity and halt the progression of ORG. However, the underlying mechanisms of their reno-protective effects in ORG remain unclear. We established a high-fat diet-induced ORG model using C57BL/6J mice, which were divided into three groups: normal chow diet (NCD group), high-fat diet (HFD) mice treated with placebo (ORG group), and HFD mice treated with empagliflozin (EMPA group). We conducted 16S ribosomal RNA gene sequencing of feces and analyzed metabolites from kidney, feces, liver, and serum samples. ORG mice showed increased urinary albumin creatinine ratio, cholesterol, triglyceride levels, and glomerular diameter compared with NCD mice (all P < 0.05). EMPA treatment significantly alleviated these parameters (all P < 0.05). Multitissue metabolomics analysis revealed lipid metabolic reprogramming in ORG mice, which was significantly altered by EMPA treatment. MetOrigin analysis showed a close association between EMPA-related lipid metabolic pathways and gut microbiota alterations, characterized by reduced abundances of Firmicutes and Desulfovibrio and increased abundance of Akkermansia (all P < 0.05). The metabolic homeostasis of ORG mice, especially in lipid metabolism, was disrupted and closely associated with gut microbiota alterations, contributing to the progression of ORG. EMPA treatment improved kidney function and morphology by regulating lipid metabolism through the gut-kidney axis, highlighting a novel therapeutic approach for ORG. NEW & NOTEWORTHY Our study uncovered that empagliflozin (EMPA) potentially protects renal function and morphology in obesity-related glomerulopathy (ORG) mice by regulating the gut-kidney axis. EMPA's reno-protective effects in ORG mice are associated with the lipid metabolism, especially in glycerophospholipid metabolism and the pantothenate/CoA synthesis pathways. EMPA's modulation of gut microbiota appears to be pivotal in suppressing glycerol 3-phosphate and CoA synthesis. The insights into gut microbiota-host metabolic interactions offer a novel therapeutic approach for ORG.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
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1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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