目的：探究用于人类局灶节段性肾小球硬化（focal segmental glomerulosclerosis，FSGS）研究的多柔比星诱导的小鼠慢性肾脏病模型的最佳方案。方法：将C57BL/6J和C57BL/6N小鼠分别按照随机数字序列进行随机分组，分为对照组（J0组和N0组，各24只）和FSGS造模组（J1组、J2组、N1组、N2组，各24只）。J1组和N1组小鼠尾静脉注射多柔比星15 mg/kg 1次，J2组和N2组注射2次（间隔2周），J0组和N0组注射等量0.9%氯化钠注射液。观察小鼠状态及体重变化，记录一般情况；收集尿液检测尿蛋白和尿肌酐，评估蛋白尿；提取肾组织蛋白行免疫印迹实验，检测足细胞标志蛋白表达。通过苏木精-伊红染色、过碘酸-希夫染色及透射电子显微镜观察各组小鼠肾组织病理表现。结果：C57BL/6N小鼠造模后一般情况较C57BL/6J小鼠差，体重下降更显著（P<0.001）。两种品系小鼠经2次注射多柔比星后，一般情况更差，体重下降更明显（P<0.001）。C57BL/6J和C57BL/6N多柔比星注射组各时间段尿蛋白/肌酐比值均高于对照组（P<0.05）。C57BL/6J单次注射组部分足细胞标志蛋白[突触足蛋白、肾母细胞瘤蛋白1（Wilms tumor protein 1，WT1）]表达无显著变化，2次注射组足细胞标志蛋白（肾病蛋白、突触足蛋白、足萼蛋白、WT1、α微管蛋白、足蛋白）表达量均较对照组降低。C57BL/6N单次及2次注射组足细胞标志蛋白表达量均较对照组降低，2次注射组下降更明显（P<0.05）。光镜和电镜均显示C57BL/6N单次及2次注射组造模成功，2次注射组病理改变更显著。结论：在多柔比星诱导的C57BL/6小鼠FSGS模型中，C57BL/6N品系造模效果优于C57BL/6J品系。推荐FSGS适宜造模方案为C57BL/6N小鼠尾静脉单次注射15 mg/kg多柔比星。

Objective To investigate the optimal protocol for a doxorubicin-induced chronic kidney disease mouse model used for studying human focal segmental glomerulosclerosis (FSGS). Methods C57BL/6J and C57BL/6N mice were randomly assigned using a random number sequence into control groups (J0 and N0, 24 mice each) and FSGS model groups (J1, J2, N1, and N2, 24 mice each). J1 and N1 groups received a single tail vein injection of 15 mg/kg doxorubicin, J2 and N2 groups received two injections (with a two-week interval), and J0 and N0 groups received an equal volume of 0.9% sodium chloride injection. The overall condition and body weight changes of the mice were observed, and general data were recorded. Urine was collected to evaluate proteinuria through urinary protein and urinary creatinine. Kidney tissue proteins were extracted for Western blot analysis to detect the expression of podocyte marker proteins. Kidney histopathological manifestations were observed using hematoxylin-eosin staining, periodic acid-Schiff staining and transmission electron microscopy. Results After modeling, C57BL/6N mice showed worse general condition and more significant weight loss than C57BL/6J mice (P<0.001). In both strains, mice receiving two doxorubicin injections showed poorer general condition and more pronounced weight loss (P<0.001). The urinary protein-to-creatinine ratio in the doxorubicin-injected groups of both C57BL/6J and C57BL/6N was higher than that in the control groups at all time points (P<0.05). In the single-injection C57BL/6J group, the expression of some podocyte marker proteins [synaptopodin, Wilms tumor protein 1 (WT1)] showed no significant changes, while in the two-injection group, the expression levels of podocyte marker proteins (nephrin, synaptopodin, podocalyxin, WT1, α-tubulin, podocin) were all lower than those in the control group. Both single- and two-injection C57BL/6N groups showed lower expression level of podocyte marker proteins than that in the control group, with more significant decreases in the two-injection group (P<0.05). Light and electron microscopy both confirmed successful modeling in the single- and two-injection C57BL/6N groups, with more significant pathological changes in the two-injection group. Conclusions In the doxorubicin-induced FSGS model in C57BL/6 mice, the C57BL/6N substrain outperforms C57BL/6J substrain in modeling efficacy. The recommended optimal modeling protocol for FSGS is the single tail vein injection of 15 mg/kg doxorubicin in C57BL/6N mice.