这项研究旨在调查肥胖相关性肾小球病(ORG)在细胞,结构,和转录组水平。将30只Wistar大鼠随机分为两组:给15只大鼠喂食标准饮食(SD大鼠),和15只大鼠饲喂高脂肪饮食(HFD-大鼠)。10周后,重量,肾功能,组织学特征,和转录组的变化进行了评估。HFD大鼠体重增加明显(55.8%vs.29.2%;p<0.001)和蛋白尿(10,384.04ng/mLvs.5845.45ng/mL;p<0.001)与SD大鼠相比。HFD-大鼠表现出ORG的早期阶段,以肾小球系膜基质增加和足细胞肥大(PH)为主。这些病变与差异表达(DE)基因和miRNA相关。功能分析显示miR-205在HFD大鼠肾脏和尿液中均为DE,负调控PTEN基因,促进足细胞的脂质内吞作用。通过SD大鼠中更高的PTEN/nephrin比率和HFD足细胞中脂质液泡的存在证明了PTEN的下调。这项研究发现了ORG早期miRNAs和基因表达的特异性靶标。此外,它强调了miR-205作为检测ORG中足细胞损伤的尿生物标志物的潜在价值,提供早期诊断的工具,并为肥胖相关性肾小球病的未来治疗研究开辟了新的途径。
This study aimed to investigate obesity-related glomerulopathy (ORG) at cellular, structural, and transcriptomic levels. Thirty Wistar rats were randomized into two groups: 15 rats were fed with a standard diet (SD-rats), and 15 rats were fed with a high-fat diet (HFD-rats). After 10 weeks, the weight, kidney function, histological features, and transcriptomic changes were assessed. HFD-rats gained significantly more weight (55.8% vs. 29.2%; p < 0.001) and albuminuria (10,384.04 ng/mL vs. 5845.45 ng/mL; p < 0.001) compared to SD-rats. HFD-rats exhibited early stages of ORG, with predominant mesangial matrix increase and podocyte hypertrophy (PH). These lesions correlated with differentially expressed (DE) genes and miRNAs. Functional analysis showed that miR-205, which was DE in both the kidneys and urine of HFD-rats, negatively regulated the PTEN gene, promoting lipid endocytosis in
podocytes. The downregulation of PTEN was proved through a higher PTEN/nephrin ratio in the SD-rats and the presence of lipid vacuoles in HFD-
podocytes. This study has found a specific targetome of miRNAs and gene expression in early stages of ORG. Also, it emphasizes the potential value of miR-205 as a urinary biomarker for detecting podocyte injury in ORG, offering a tool for early diagnosis, and opening new avenues for future therapeutic research of obesity-related glomerulopathy.