Kato Takashi, Kurosawa Tsutomu Miki, Taketo Makoto Mark
The Institute of Experimental Animal Sciences, Osaka University Medical School, Suita, Japan.
Ren Fail. 2009;31(3):229-38. doi: 10.1080/08860220802669834.
ICGN/Oa mice are used to study the pathophysiological mechanisms underlying proteinuria-induced chronic kidney disease (CKD). Recently, a mutation of tensin2 gene (Tns2) was suggested to be responsible for proteinuria in the inbred ICGN mice. We identified the wild-type (+/+), heterozygous (+/nep), and homozygous (nep/nep) ICGN/Oa mice by PCR assay. The homozygotes developed proteinuria, resulting in nephrotic syndrome (NS) as early as 5 weeks and CKD by 15 weeks. However, the heterozygotes did not show the symptoms of these renal failures. These results indicate that the homozygous tensin2 mutation is necessary for the ICGN/Oa mice to develop proteinuria-induced CKD. Furthermore, we examined the time course of tubulointerstitial fibrosis and the kinetics of tubular epithelial cells (TECs) in the ICGN/Oa mice using immunohistochemical and TUNEL assays. In the renal parenchyma of the five-week-old homozygotes, the expression of alpha-SMA and type I collagen were higher than those in the age-matched wild-type. Additionally, increased TEC proliferation was found at 5 weeks, and increased TEC apoptosis was by 15 weeks in the homozygotes. Tubulointerstitial fibrosis precedes TEC apoptosis in the proteinuria-induced CKD model mice, and that tubulointerstitial fibrosis may be the triggering event of the disease.
ICGN/Oa小鼠被用于研究蛋白尿诱导的慢性肾脏病（CKD）的病理生理机制。最近，有人提出张力蛋白2基因（Tns2）的突变是导致近交系ICGN小鼠蛋白尿的原因。我们通过PCR检测鉴定了野生型（+/+）、杂合子（+/nep）和纯合子（nep/nep）的ICGN/Oa小鼠。纯合子早在5周龄时就出现蛋白尿，进而导致肾病综合征（NS），到15周龄时发展为CKD。然而，杂合子并未出现这些肾衰竭症状。这些结果表明，纯合的张力蛋白2突变是ICGN/Oa小鼠发生蛋白尿诱导的CKD所必需的。此外，我们使用免疫组织化学和TUNEL检测方法，研究了ICGN/Oa小鼠肾小管间质纤维化的时间进程和肾小管上皮细胞（TECs）的动力学。在5周龄纯合子的肾实质中，α-SMA和I型胶原蛋白的表达高于年龄匹配的野生型。此外，在5周龄时发现纯合子的TEC增殖增加，到15周龄时TEC凋亡增加。在蛋白尿诱导的CKD模型小鼠中，肾小管间质纤维化先于TEC凋亡发生，并且肾小管间质纤维化可能是该疾病的触发事件。
