High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy
High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy
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DOI：
10.1073/pnas.1600511113
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发表时间：
2016-02-23
影响因子：
11.1
通讯作者：
Kakoki, Masao
中科院分区：
文献类型：
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作者：
Hathaway, Catherine K.;Chang, Albert S.;Kakoki, Masao
人类全基因组关联研究表明，包裹体和细胞运动蛋白1基因(ELMO1)的多态与糖尿病肾病的易感性密切相关。然而，缺乏因果关系的证据。为了测试其表达的轻微变化是否会改变糖尿病小鼠肾脏表型的严重性，我们产生了1型糖尿病小鼠，因为它们具有Ins2(Akita)基因，并且ELMO1在所有组织中的基因分级表达分为五个步骤，从类似于30%到类似于200%正常。我们在这里显示ELMO1多形体有蛋白尿、肾小球硬化和肾小球基底膜超微结构的改变，这些改变的严重程度与ELMO1的表达平行。肾脏转化生长因子β1、内皮素-1和NAD(P)H氧化酶4的mRNA表达的进行性变化也与ELMO1同步发生，血浆胱抑素C、过氧化脂质和转化生长因子β1的水平以及红细胞还原型谷胱甘肽的水平也随之发生变化。相比之下，ELMO1表达低于正常的秋田1型糖尿病小鼠，这些不同因素的表达减少，糖尿病并发症也较少。值得注意的是，ELMO1在30%亚型中的表达减少几乎消除了糖尿病肾病的病理特征，尽管它不影响秋田突变引起的高血糖。因此，ELMO1在1型糖尿病肾病的发生发展中起着重要作用，其抑制作用可能成为延缓或阻止疾病进展为终末期肾病的一个有前途的选择。
Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2(Akita) gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from similar to 30% to similar to 200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo1. Progressive changes in renal mRNA expression of transforming growth factor beta 1 (TGF beta 1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGF beta 1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.