Yang Rui, Chen Rongping, Xu Ningning, Yang Xiaoyan, Chen Hong
Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Ave, Guangzhou, Guangdong province, China.
Cell Biol Toxicol. 2025 Jun 26;41(1):108. doi: 10.1007/s10565-025-10060-4.
As a primary contributor to end-stage renal disease, diabetic kidney disease (DKD) is characterized by metabolic and inflammatory disturbances. Emerging evidence highlights the gut microbiota's contribution to DKD through metabolite interactions. This study investigates the role of the gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) and its inhibition of the protease serine 3 (PRSS3) gene in DKD progression.
Fecal and blood samples from 22 DKD and 22 non-diabetic kidney disease (NDKD) patients were analyzed using 16S rRNA sequencing and LC/MS-based metabolomics. Differential gene expression was analyzed using public datasets. Molecular docking assessed TMAO-PRSS3 interactions. In vitro studies employed high-glucose treatments and TMAO exposure in HK-2 renal epithelial cells, while in vivo DKD models were induced in mice using streptozotocin. Functional roles of PRSS3 were validated through lentiviral overexpression and adeno-associated virus delivery.
Gut microbiota analysis revealed reduced diversity and abundance in DKD patients, with altered bacterial taxa associated with increased TMAO production. Metabolomics identified TMAO as a significant metabolite, targeting PRSS3 and reducing its expression in renal cells. Molecular docking confirmed direct TMAO-PRSS3 binding. PRSS3 overexpression mitigated high-glucose- and TMAO-induced renal cell damage and inflammation in vitro and fibrosis in DKD mouse models. However, TMAO partially attenuated PRSS3's protective effects.
This study identifies TMAO as a key mediator of DKD progression through PRSS3 inhibition. Enhancing PRSS3 expression protects against renal damage, highlighting its potential as a therapeutic target. Modulating gut microbiota and TMAO levels offers promising avenues for DKD management.
作为终末期肾病的主要病因，糖尿病肾病（DKD）的特征是代谢和炎症紊乱。新出现的证据突出了肠道微生物群通过代谢物相互作用对DKD的影响。本研究调查了肠道微生物群衍生的代谢物氧化三甲胺（TMAO）及其对蛋白酶丝氨酸3（PRSS3）基因的抑制在DKD进展中的作用。
对22例DKD患者和22例非糖尿病肾病（NDKD）患者的粪便和血液样本进行16S rRNA测序和基于液相色谱/质谱的代谢组学分析。使用公共数据集分析差异基因表达。分子对接评估TMAO与PRSS3的相互作用。体外研究采用高糖处理和TMAO处理HK-2肾上皮细胞，而体内DKD模型则通过链脲佐菌素诱导小鼠建立。通过慢病毒过表达和腺相关病毒递送验证PRSS3的功能作用。
肠道微生物群分析显示，DKD患者的微生物多样性和丰度降低，与TMAO产生增加相关的细菌类群发生改变。代谢组学确定TMAO是一种重要的代谢物，靶向PRSS3并降低其在肾细胞中的表达。分子对接证实了TMAO与PRSS3的直接结合。PRSS3过表达减轻了高糖和TMAO诱导的体外肾细胞损伤和炎症以及DKD小鼠模型中的纤维化。然而，TMAO部分减弱了PRSS3的保护作用。
本研究确定TMAO是通过抑制PRSS3导致DKD进展的关键介质。增强PRSS3表达可预防肾损伤，突出了其作为治疗靶点的潜力。调节肠道微生物群和TMAO水平为DKD管理提供了有前景的途径。
