Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China.
Food Funct. 2019 May 22;10(5):2970-2985. doi: 10.1039/c8fo01653d.
Obesity-related renal disease is related to caloric excess promoting deleterious cellular responses. However, a full understanding of the molecular mechanisms involved in progressive kidney disease, as well as a therapeutic strategy, is still absent. Fisetin (FIS), as a natural flavonoid, possesses various bioactivities in a number of disease models. However, its role in obesity-associated kidney injury is still unclear and requires elucidation. In our study, an obesity animal model was established using C57BL/6 mice fed with a normal chow diet (NCD) or high fat diet (HFD) for 16 weeks with or without FIS administration (20, 40 or 80 mg kg-1). Our results indicated that chronic HFD feeding led to a significant body weight gain in mice compared to the normal control group, accompanied by a marked insulin resistance and glucose intolerance, whereas FIS treatment exerted prominently protective effects. In addition, FIS significantly attenuated HFD-induced histological alterations in renal tissue samples. Moreover, FIS treatment down-regulated expression of kidney injury molecule-1 (KIM-1), and up-regulated nephrin and podocin expression levels in the kidneys of HFD-fed mice, improving their renal dysfunction. After HFD feeding, mice treated with FIS exhibited a decrease in phosphorylated IRS1Ser307, and an increase in phosphorylated glycogen synthase kinase 1 (IRS1Tyr608), AKT, forkhead box protein O1 (FOXO1) and glycogen synthase kinase (GSK)-3β. Furthermore, FIS administration markedly restrained the inflammatory response in the kidneys of HFD-challenged mice, as evidenced by the reduced pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-1β and IL-18, which was attributed to the blockage of nuclear factor κB (NF-κB) signaling. Importantly, FIS-treated obese mice exerted a remarkable decrease in RIP3 expressions in the kidneys compared to obese mice in the absence of FIS, along with an evident reduction in the NOD-like receptor protein 3 (NLRP3), an apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1. The protective effects of FIS against HFD-induced renal injury were verified in vitro using palmitate (PAL)-treated HK2 cells, an immortalized proximal tubule epithelial cell line from the adult human kidney. In summary, our results supported the notion that FIS functions as a promising agent to improve insulin resistance and inflammatory response against metabolic stress-induced renal injury.
肥胖相关的肾脏疾病与热量过剩引起的有害细胞反应有关。然而，对于进展性肾病的分子机制，以及治疗策略，我们仍然缺乏全面的了解。漆黄素（FIS）作为一种天然类黄酮，在多种疾病模型中具有多种生物活性。然而，它在肥胖相关肾损伤中的作用尚不清楚，需要进一步阐明。在我们的研究中，使用 C57BL/6 小鼠建立了肥胖动物模型，这些小鼠用正常饲料（NCD）或高脂肪饮食（HFD）喂养 16 周，同时给予或不给予 FIS 治疗（20、40 或 80mg/kg）。我们的结果表明，与正常对照组相比，慢性 HFD 喂养导致小鼠体重显著增加，同时伴有明显的胰岛素抵抗和葡萄糖不耐受，而 FIS 治疗则表现出明显的保护作用。此外，FIS 显著减轻了 HFD 诱导的肾组织样本的组织学改变。此外，FIS 治疗下调了肥胖饮食喂养小鼠肾脏中肾损伤分子-1（KIM-1）的表达，并上调了肾脏中nephrin 和 podocin 的表达水平，改善了其肾功能障碍。在 HFD 喂养后，用 FIS 治疗的小鼠表现出 IRS1Ser307 的磷酸化减少，IRS1Tyr608 的磷酸化增加，AKT、叉头框蛋白 O1（FOXO1）和糖原合酶激酶（GSK）-3β。此外，FIS 给药显著抑制了 HFD 应激小鼠肾脏的炎症反应，这表现为促炎细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素 6（IL-6）、白细胞介素 1β（IL-1β）和白细胞介素 18（IL-18）的减少，这归因于核因子 κB（NF-κB）信号的阻断。重要的是，与没有 FIS 的肥胖小鼠相比，用 FIS 治疗的肥胖小鼠肾脏中的 RIP3 表达明显减少，同时 NOD 样受体蛋白 3（NLRP3）、凋亡相关斑点样蛋白含有 Caspase 募集域（ASC）和 Caspase-1 也明显减少。FIS 对 HFD 诱导的肾损伤的保护作用在体外使用棕榈酸（PAL）处理的 HK2 细胞中得到了验证，HK2 细胞是一种来源于成人肾脏的永生化近端肾小管上皮细胞系。总之，我们的研究结果支持了 FIS 作为一种有前途的药物，可以改善胰岛素抵抗和炎症反应，对抗代谢应激引起的肾损伤的观点。
