Gen1 Modulates Metanephric Morphology Through Retinoic Acid Signaling
Gen1 Modulates Metanephric Morphology Through Retinoic Acid Signaling
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Gen1 通过视黄酸信号调节后肾形态
DOI：
10.1089/dna.2018.4426
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发表时间：
2019
影响因子：
3.1
通讯作者：
Shen Qian
中科院分区：
文献类型：
--
作者：
Zhang Ya;Zhang Xin;Wang Xiaowen;Wang Herui;Wu Xiaohui;Xu Hong;Shen Qian
先天性肾脏和尿路异常（ckut）是儿童终末期肾脏疾病的主要原因。我们的团队已经发现Holliday Junction resolve - vase基因gen1是CAKUT的潜在候选基因。gen1突变小鼠的CAKUT表型与维甲酸（RA）缺陷模型相似。编码RA合成关键酶的Raldh2通过RNA测序在ingen1突变体后肾细胞中表达减少。通过实时逆转录pcr检测，Raldh2和下游Ret在胚胎期(E) 11.5 gen1突变体输尿管和E13.5肾脏中表达降低，RA受体α在E13.5 gen1突变体输尿管和肾脏中表达降低。进一步的研究表明，全反式维甲酸（ATRA）挽救了孤立肾表型，改善了输尿管分支；输尿管出芽后应给予ATRA，以避免增加异位出芽的发生率。转染Gen1 siRNA的CHO-K1细胞中RA反应元件的荧光素酶强度低于转染打乱RNA的CHO-K1细胞，这种抑制作用可以被ATRA逆转。这些发现表明，gen1突变可通过RA信号通路导致肾脏畸形，而gen1缺失诱导的ckut可通过ATRA部分修复。
Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end-stage renal disease in children. Our group has discovered that Holliday Junction resolvase geneGen1is a potential candidate gene for CAKUT.Gen1mutant mice showed CAKUT phenotypes similar to those observed in retinoic acid (RA)-deficient models. The expression of Raldh2, which encodes the key enzyme in RA synthesis, was reduced inGen1mutant metanephros through RNA sequencing. By real-time reverse transcription-PCR, the expression of both Raldh2 and downstream Ret was reduced in embryonic day (E) 11.5Gen1mutant ureters and E13.5 kidneys, and expression of RA receptor alpha was decreased in E13.5Gen1mutant ureters and kidneys. Further studies showed that all-trans retinoic acid (ATRA) rescued solitary kidney phenotype and improved ureteric branching; ATRA should be administered after ureteric budding to avoid increasing the incidence of ectopic budding inGen1mutants. Luciferase intensity of RA response element was lower in CHO-K1 cells transfected with Gen1 siRNA than in those transfected with scrambled RNA, and this inhibitory effect could be reversed by ATRA. These findings indicate thatGen1mutation can result in renal malformation through RA signaling and Gen1-loss-induced CAKUT can be partly rescued by ATRA.