An inducible mouse model of podocin-mutation-related nephrotic syndrome.
An inducible mouse model of podocin-mutation-related nephrotic syndrome.
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DOI：
10.1371/journal.pone.0186574
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Schaefer F
中科院分区：
文献类型：
--
作者：
Tabatabaeifar M;Wlodkowski T;Simic I;Denc H;Mollet G;Weber S;Moyers JJ;Brühl B;Randles MJ;Lennon R;Antignac C;Schaefer F
编码podocin的NPHS2基因突变会导致遗传性肾病综合征。最常见的podocin突变R138Q与早期发病和快速进展为终末期肾病有关。携带R140Q突变(类似于人类R138Q的小鼠)的敲入小鼠在新生年龄表现出足细胞发育停滞和致命的肾功能衰竭。在这里，我们使用三苯氧胺诱导的Cre重组酶创建了一个名为NPHS2 R140Q/-的条件性Podocin敲入模型，该模型允许研究突变对出生后生活的影响。在R140Q诱导的第一周内，动物出现蛋白尿，在4-5周后达到高峰。随后，动物发生进行性肾功能衰竭，中位生存期为12周(95%可信区间：11-13周)。足突融合在一周内被观察到，在病程中进展到严重的和全局的消失。诱导后12-16周，每个肾小球的足细胞数量逐渐减少到健康对照组的18%。2、4、8周节段性硬化肾小球比例分别为25%、85%、97%。严重的肾小管间质纤维化出现在疾病的晚期，并与疾病早期的蛋白尿水平呈定量相关。诱导后1周，R140Q podocin基因表达增加，蛋白丰度降低50%以上。MiRNA21的表达在诱导后的前4周持续升高，而miRNA-193a的表达在诱导后2周达到高峰。总之，可诱导的R140Q-podocin小鼠模型是人类肾病综合征最常见遗传原因的吉祥模型，其自发疾病过程强烈地让人想起人类的疾病。该模型是测试旨在改善足细胞功能和活性、减轻蛋白尿、肾小球硬化和进行性肾功能衰竭的新型药物干预措施有效性的有价值的工具。
Mutations in the NPHS2 gene, encoding podocin, cause hereditary nephrotic syndrome. The most common podocin mutation, R138Q, is associated with early disease onset and rapid progression to end-stage renal disease. Knock-in mice carrying a R140Q mutation, the mouse analogue of human R138Q, show developmental arrest of podocytes and lethal renal failure at neonatal age. Here we created a conditional podocin knock-in model named NPHS2 R140Q/-, using a tamoxifen-inducible Cre recombinase, which permits to study the effects of the mutation in postnatal life. Within the first week of R140Q hemizygosity induction the animals developed proteinuria, which peaked after 4–5 weeks. Subsequently the animals developed progressive renal failure, with a median survival time of 12 (95% CI: 11–13) weeks. Foot process fusion was observed within one week, progressing to severe and global effacement in the course of the disease. The number of podocytes per glomerulus gradually diminished to 18% compared to healthy controls 12–16 weeks after induction. The fraction of segmentally sclerosed glomeruli was 25%, 85% and 97% at 2, 4 and 8 weeks, respectively. Severe tubulointerstitial fibrosis was present at later disease stage and was correlated quantitatively with the level of proteinuria at early disease stages. While R140Q podocin mRNA expression was elevated, protein abundance was reduced by more than 50% within one week following induction. Whereas miRNA21 expression persistently increased during the first 4 weeks, miRNA-193a expression peaked 2 weeks after induction. In conclusion, the inducible R140Q-podocin mouse model is an auspicious model of the most common genetic cause of human nephrotic syndrome, with a spontaneous disease course strongly reminiscent of the human disorder. This model constitutes a valuable tool to test the efficacy of novel pharmacological interventions aimed to improve podocyte function and viability and attenuate proteinuria, glomerulosclerosis and progressive renal failure.