Cao Xinxin, Yao Fan, Liu Wenxiu, Wang Yufang, Zhang Zhen, Zhang Chongyang, Dong Zhengqi, Zhang Bin, He Ruikun, Sun Xiaobo
Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China.
Front Pharmacol. 2025 Apr 8;16:1541947. doi: 10.3389/fphar.2025.1541947. eCollection 2025.
Diabetic nephropathy (DN), one of the serious complications in the diabetes, has a high mortality in the diabetic patients. Bilberry ( L.) have received much attention for their health benefits in alleviating metabolic diseases, which are rich in anthocyanins. However, the anti-DN ability of bilberry has not been fully studied. The aim of this study was to investigate the effect and mechanism of L. extract (VCE) on diabetic nephropathy and .
Streptozocin (STZ) combined with high fat induced DN model was established in rats. Biochemical indicators, histopathology, 16s third generation sequencing and serum metabolomics were used to evaluate the effects of VCE on DN. Subsequently, a cell model of advanced glycation end products (AGEs) induced podocyte injury was established to verify which compounds in VCE played the main anti-diabetic nephropathy function and the mechanism of action. Finally, experiments were conducted to verify the effect of characteristic metabolites screened by serum metabolomics on improving diabetic nephropathy.
Insulin resistance index, lipid metabolism, oxidative stress and inflammatory response indexes of DN rats were significantly improved after 8 weeks of VCE treatment. In addition, intake of VCE modulates gut microbiota composition and reverses the abundance of , and . Supplementation with VCE altered serum metabolite levels, including uridine and phenylacetylglycine. Pretreatment with VCE and its anthocyanins inhibited the expression of LDH, IL-6 and TNF-α, reduced the levels of p38-MAPK, IĸBα, IKKβ, and NF-κB in podocyte cells. In addition, pretreatment with serum metabolite uridine also reduced the expression of LDH and mitochondrial ROS, and inhibited cell apoptosis.
Our findings suggest that the improvement of gut microbiota and metabolic function were related to the anti-DN potential of VCE, and the underlying mechanism may be related to the inhibition of MAPK/NF-κB signaling pathway.
糖尿病肾病（DN）是糖尿病严重并发症之一，糖尿病患者死亡率较高。越橘因富含花青素，对缓解代谢性疾病有益健康而备受关注。然而，越橘的抗糖尿病肾病能力尚未得到充分研究。本研究旨在探讨越橘提取物（VCE）对糖尿病肾病的作用及其机制。
采用链脲佐菌素（STZ）联合高脂诱导大鼠糖尿病肾病模型。运用生化指标、组织病理学、16S第三代测序和血清代谢组学评估VCE对糖尿病肾病的影响。随后，建立晚期糖基化终产物（AGEs）诱导足细胞损伤的细胞模型，以验证VCE中哪些化合物发挥主要抗糖尿病肾病作用及其作用机制。最后，进行实验验证血清代谢组学筛选出的特征性代谢物对改善糖尿病肾病的作用。
VCE治疗8周后，糖尿病肾病大鼠的胰岛素抵抗指数、脂质代谢、氧化应激和炎症反应指标均显著改善。此外，摄入VCE可调节肠道微生物群组成，并逆转特定菌属的丰度。补充VCE可改变血清代谢物水平，包括尿苷和苯乙酰甘氨酸。VCE及其花青素预处理可抑制足细胞中乳酸脱氢酶（LDH）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的表达，降低p38丝裂原活化蛋白激酶（p38-MAPK）、核因子κB抑制蛋白α（IĸBα）、IκB激酶β（IKKβ）和核因子κB（NF-κB）的水平。此外，血清代谢物尿苷预处理也可降低LDH的表达和线粒体活性氧水平，并抑制细胞凋亡。
我们的研究结果表明，肠道微生物群和代谢功能的改善与VCE的抗糖尿病肾病潜力有关，其潜在机制可能与抑制丝裂原活化蛋白激酶/核因子κB（MAPK/NF-κB）信号通路有关。
