Genetic Analysis of Mesangial Matrix Expansion in Aging Mice and Identification of Far2 as a Candidate Gene
Genetic Analysis of Mesangial Matrix Expansion in Aging Mice and Identification of Far2 as a Candidate Gene
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DOI：
10.1681/asn.2012080838
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发表时间：
2013-12-01
影响因子：
13.6
通讯作者：
Korstanje, Ron
中科院分区：
文献类型：
--
作者：
Noordmans, Gerda A.;Caputo, Christina R.;Korstanje, Ron
肾脏的老化与肾损伤有关，特别是系膜基质扩张（MME）。确定参与这一过程的基因将有助于揭示衰老的机制，并有助于设计旨在预防和回归的新型治疗方法。在这项研究中，肾小球的结构变化的24个近交系小鼠品系的特点是在雄性小鼠在6个月，12个月和20个月的年龄。单倍型关联作图用于确定与20个月时存在MME相关的遗传基因座。该分析确定了与6号染色体上含有Far 2的200 kb单倍型块的显著关联。测序结果显示，小鼠品系与MME含有一个9 bp的序列在5个非翻译区的Far 2是不存在的大多数菌株没有MME。实时PCR显示，在肾脏中的插入片段的菌株的Far 2的表达增加了两倍，随后的实验中进行的体外荧光素酶报告载体表明，这种序列差异导致差异表达的Far 2。在小鼠系膜细胞系中Far 2的过表达诱导血小板活化因子和纤维化标志物TGF-β的上调。MME促进因子的这种上调可能部分地由FAR 2催化的脂肪酰辅酶A还原成脂肪醇（其可能是血小板活化因子的前体）引起。总体而言，这些数据表明鉴定了一种参与肾老化的新途径，该途径可能产生减少MME的治疗靶点。
Aging of the kidney is associated with renal damage, in particular mesangial matrix expansion (MME). Identifying the genes involved in this process will help to unravel the mechanisms of aging and aid in the design of novel therapeutic modalities aimed at prevention and regression. In this study, structural changes in glomeruli of 24 inbred mouse strains were characterized in male mice at 6, 12, and 20 months of age. Haplotype association mapping was used to determine genetic loci associated with the presence of MME at 20 months. This analysis identified a significant association with a 200-kb haplotype block on chromosome 6 containing Far2. Sequencing revealed that mouse strains with MME contain a 9-bp sequence in the 5 untranslated region of Far2 that is absent in most of the strains without MME. Real-time PCR showed a two-fold increase in the expression of Far2 in the kidneys of strains with the insert, and subsequent experiments performed in vitro with luciferase reporter vectors showed that this sequence difference causes differential expression of Far2. Overexpression of Far2 in a mouse mesangial cell line induced upregulation of platelet activating factor and the fibrotic marker TGF-. This upregulation of MME-promoting factors may result, in part, from the FAR2-catalyzed reduction of fatty acyl-coenzyme A to fatty alcohols, which are possible precursors of platelet activating factor. Overall, these data suggest the identification of a novel pathway involved in renal aging that may yield therapeutic targets for reducing MME.