Genetic mapping of renal glutathione suggests a novel regulatory locus on the murine X chromosome and overlap with hepatic glutathione regulation.
Genetic mapping of renal glutathione suggests a novel regulatory locus on the murine X chromosome and overlap with hepatic glutathione regulation.
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DOI：
10.1016/j.freeradbiomed.2021.07.035
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发表时间：
2021-10
影响因子：
7.4
通讯作者：
Pazdro R
中科院分区：
文献类型：
--
作者：
Gould RL;Craig SW;McClatchy S;Churchill GA;Pazdro R
谷胱甘肽（GSH）是一种重要的细胞抗氧化剂，可防止有氧代谢和其他反应性亲电体的副产物，以防止氧化应激和细胞死亡。适当维持其还原形式GSH超过其氧化形式GSSG，可防止肾脏中的氧化应激，并防止慢性肾脏疾病的发展。有证据表明，肾脏中GSH和GSSG的浓度，以及它们的比值GSH/GSSG，是中度遗传的，过去的研究已经确定了多态性和候选基因与小鼠这些表型。然而，这些发现是通过计算机绘图方法进行的，这些方法容易出现假阳性和功率限制，因此控制肾脏谷胱甘肽的真实位点和候选基因仍然未知。本研究利用高分辨率基因定位与多样性远交小鼠股票，以确定潜在的变化，肾脏谷胱甘肽水平和氧化还原状态的致病基因座。定位结果在小鼠X染色体上51.602 Mbp处发现了一个与肾GSH相关的暗示性位点，生物信息学分析将骨化诱导因子α相关1（Aifm 1）确定为最合理的候选者。然后，映射输出进行编译和比较对肝脏GSH系统的遗传结构，我们发现了小鼠染色体14上的一个位点，肝脏GSH浓度和肾脏GSH氧化还原电位之间的重叠。总的来说，这些结果支持我们以前提出的模型，即GSH氧化还原系统受全球和组织特异性位点的调控，大大提高了我们对GSH及其调控的理解，并为未来的机制研究提出了新的候选基因。
Glutathione (GSH) is a critical cellular antioxidant that protects against byproducts of aerobic metabolism and other reactive electrophiles to prevent oxidative stress and cell death. Proper maintenance of its reduced form, GSH, in excess of its oxidized form, GSSG, prevents oxidative stress in the kidney and protects against the development of chronic kidney disease. Evidence has indicated that renal concentrations of GSH and GSSG, as well as their ratio GSH/GSSG, are moderately heritable, and past research has identified polymorphisms and candidate genes associated with these phenotypes in mice. Yet those discoveries were made with in silico mapping methods that are prone to false positives and power limitations, so the true loci and candidate genes that control renal glutathione remain unknown. The present study utilized high-resolution gene mapping with the Diversity Outbred mouse stock to identify causal loci underlying variation in renal GSH levels and redox status. Mapping output identified a suggestive locus associated with renal GSH on murine chromosome X at 51.602 Mbp, and bioinformatic analyses identified apoptosis-inducing factor mitochondria-associated 1 (Aifm1) as the most plausible candidate. Then, mapping outputs were compiled and compared against the genetic architecture of the hepatic GSH system, and we discovered a locus on murine chromosome 14 that overlaps between hepatic GSH concentrations and renal GSH redox potential. Overall, the results support our previously proposed model that the GSH redox system is regulated by both global and tissue-specific loci, vastly improving our understanding of GSH and its regulation and proposing new candidate genes for future mechanistic studies.
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影响因子：
2.5
作者：
Churchill, Gary A.;Gatti, Daniel M.;Munger, Steven C.;Svenson, Karen L.
通讯作者：
Svenson, Karen L.
影响因子：
11.1
作者：
Bano D;Prehn JHM
通讯作者：
Prehn JHM
影响因子：
10.6
作者：
Forman, Henry Jay;Zhang, Hongqiao;Rinna, Alessandra
通讯作者：
Rinna, Alessandra
影响因子：
3.7
作者：
Bénit P;Goncalves S;Dassa EP;Brière JJ;Rustin P
通讯作者：
Rustin P
影响因子：
14.9
作者：
Blake JA;Eppig JT;Kadin JA;Richardson JE;Smith CL;Bult CJ;the Mouse Genome Database Group
通讯作者：
the Mouse Genome Database Group