Centre for Diabetes Research, Harry Perkins Institute of Medical Research, the University of Western Australia, Perth, Western Australia, Australia; School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, Western Australia, Australia.
Centre for Diabetes Research, Harry Perkins Institute of Medical Research, the University of Western Australia, Perth, Western Australia, Australia.
Kidney Int. 2019 Oct;96(4):918-926. doi: 10.1016/j.kint.2019.04.031. Epub 2019 May 30.
Genetic factors influence susceptibility to diabetic kidney disease. Here we mapped genes mediating renal hypertrophic changes in response to diabetes. A survey of 15 mouse strains identified variation in diabetic kidney hypertrophy. Strains with greater (FVB/N(FVB)) and lesser (C57BL/6 (B6)) responses were crossed and diabetic F2 progeny were characterized. Kidney weights of diabetic F2 mice were broadly distributed. Quantitative trait locus analyses revealed diabetic mice with kidney weights in the upper quartile shared alleles on chromosomes (chr) 6 and 12; these loci were designated as Diabetic kidney hypertrophy (Dkh)-1 and -2. To confirm these loci, reciprocal congenic mice were generated with defined FVB chromosome segments on the B6 strain background (B6.Dkh1/2f) or vice versa (FVB.Dkh1/2b). Diabetic mice of the B6.Dkh1/2f congenic strain developed diabetic kidney hypertrophy, while the reciprocal FVB.Dkh1/2b congenic strain was protected. The chr6 locus contained the candidate gene; Ark1b3, coding aldose reductase; the FVB allele has a missense mutation in this gene. Microarray analysis identified differentially expressed genes between diabetic B6 and FVB mice. Thus, since the two loci identified by quantitative trait locus mapping are syntenic with regions identified for human diabetic kidney disease, the congenic strains we describe provide a valuable new resource to study diabetic kidney disease and test agents that may prevent it.
遗传因素影响糖尿病肾病的易感性。在这里，我们绘制了介导糖尿病时肾脏肥大变化的基因图谱。对 15 种小鼠品系的调查发现了糖尿病肾病肥大的变异。具有更大（FVB/N[FVB]）和更小（C57BL/6[B6]）反应的品系进行杂交，并且对糖尿病 F2 后代进行了特征描述。糖尿病 F2 小鼠的肾脏重量广泛分布。数量性状基因座分析显示，糖尿病肾脏重量处于四分位数上限的小鼠在染色体 6 和 12 上共享等位基因；这些基因座被指定为糖尿病肾脏肥大（Dkh）-1 和 -2。为了确认这些基因座，在 B6 背景上用定义的 FVB 染色体片段生成了相互的同源基因小鼠（B6.Dkh1/2f）或反之亦然（FVB.Dkh1/2b）。B6.Dkh1/2f 同源基因小鼠的糖尿病小鼠发生了糖尿病肾脏肥大，而相反的 FVB.Dkh1/2b 同源基因小鼠受到保护。chr6 基因座包含候选基因；Ark1b3，编码醛糖还原酶；FVB 等位基因在这个基因中有一个错义突变。微阵列分析鉴定了糖尿病 B6 和 FVB 小鼠之间差异表达的基因。因此，由于通过数量性状基因座作图鉴定的两个基因座与鉴定为人类糖尿病肾病的区域是同线性的，我们描述的同源基因小鼠提供了一个宝贵的新资源来研究糖尿病肾病并测试可能预防该病的药物。
