| Abstract (English): |
AIM: This study investigates the protective effect of the selective peroxisome proliferator-activated receptor δ (PPARδ) agonist seladelpar on podocytes in a mouse model of diabetic kidney disease (DKD). METHODS: A DKD mouse model was established using streptozotocin and a high-fat diet. Mice were randomly assigned to three groups: control, DKD with vehicle treatment, and DKD with seladelpar treatment at dosages of 1, 5 and 10 mg/kg(6 to 7 mice per group). After four weeks of treatment, mice were euthanized, and various parameters were measured, including urinary albumin, creatinine, blood urea nitrogen, serum triglycerides, and cholesterol using respective kits. Renal tissues were processed for histological examination through HE and PAS staining to assess glomerular pathology. The RNA from glomerular tissues was analyzed via RT-qPCR for podocyte marker (Nphs1, Nphs2, Wt1 and Synpo) expression, and the protein expression was evaluated using Western blot for PPARδ. Immunofluorescence staining of frozen renal cortical sections was conducted to quantify WT1-positive cells and desmin protein levels. Transmission electron microscopy was used to observe glomerular ultrastructural changes. RESULTS: (1) PPARδ protein levels in the glomerular tissue of DKD mice were significantly lower than in controls. (2) Mice treated with 10 mg/kg of seladelpar showed reduced blood glucose, triglycerides, and cholesterol levels compared to the diabetic nephropathy group.(3) Both 5 mg/kg and 10 mg/kg seladelpar treatment groups exhibited decreased urine albumin/creatinine ratios, along with improvements in glomerular hy-pertrophy and mesangial matrix deposition. Increased mRNA expression levels of Nphs1, Nphs2, Wt1, and Synpo were also observed, alongside an increase in WT1-positive cells and a decrease in desmin expression. Additionally, there was a reduction in podocyte foot process fusion and glomerular basement membrane thickness. (4) RNA sequencing indicated that 5 mg/kg seladelpar treatment modulated PPAR signaling pathway and influenced various metabolic pathways, including bile acid metabolism, carbon metabolism, glutathione metabolism, glycerophospholipid metabolism, and fatty acid metabolism. CONCLUSION: Seladelpar, a PPARδ agonist, mitigates podocyte injury and reduces proteinuria in DKD mice. Notably, the protective effects of seladelpar are partially independent of its hypolipidemic properties. [ABSTRACT FROM AUTHOR] |
| Abstract (Chinese): |
目的: 分析选择性过氧化物酶体增殖物激活受体δ(PPARδ)激动剂seladelpar对糖尿病肾病(DKD) 小鼠足细胞的保护作用。方法: 采用链脲佐菌素联合高脂饲料喂养构建DKD小鼠模型。小鼠被随机分为对照组、 DKD组(予以生理盐水处理)及DKD+seladelpar(1、5和10 mg/kg)治疗组, 每组小鼠6~7只。治疗4周后处死小鼠, 分 别使用Albuwell M酶联免疫吸附测定试剂盒、肌酐试剂盒、血尿素氮试剂盒、甘油三酯试剂盒和胆固醇试剂盒检测 各组小鼠的尿微量白蛋白、尿肌酐、血尿素氮、血甘油三酯和血胆固醇的浓度。肾脏组织脱水包埋制作石蜡切片用 于HE和PAS染色分析肾小球的病理改变。肾小球组织采用RNA测序和RT-qPCR法检测足细胞标志物Nphs1、 Nphs2、Wt1和Synpo的mRNA表达量, Western blot检测PPARδ蛋白表达。肾皮质组织制作冰冻切片用于免疫荧光 染色检测Wilms肿瘤蛋白1(WT1)阳性细胞数和desmin蛋白表达。透射电镜下观察小鼠足细胞超微结构改变。结 果: (1)与对照组相比, DKD组小鼠肾小球组织PPARδ蛋白的表达量降低。(2)与DKD组相比, seladelpar 10 mg/kg 治疗组小鼠的血糖、血甘油三酯和血胆固醇的浓度降低。(3)与DKD组相比, seladelpar 5 mg/kg和10 mg/kg治疗组小 鼠的尿白蛋白/肌酐比值降低;肾小球肥大和系膜区基质沉积缓解;Nphs1、Nphs2、Wt1和Synpo的mRNA表达量升 高;肾小球WT1阳性细胞数增加, desmin表达下降;足细胞足突融合度和肾小球基底膜厚度降低。(4)RNA测序结果 显示, seladelpar 5 mg/kg治疗组能够调控PPAR信号通路, 并参与多种代谢途径的调节, 包括胆酸代谢、碳水化合物 代谢、谷胱甘肽代谢、甘油磷脂代谢及脂肪酸代谢等。结论: PPARδ激动剂seladelpar能够减轻DKD小鼠的足细胞 损伤, 并降低尿液中白蛋白的排泄, 其对DKD小鼠的保护作用在一定程度上独立于其降血脂效果. [ABSTRACT FROM AUTHOR] |