Department of Pediatrics, Montreal Children's Hospital Research Institute, McGill University, and Département de Médecine, Centre Hospitalier de l'Université de Montréal,Montreal, Quebec, Canada.
Kidney Int. 2010 Jul;78(1):96-102. doi: 10.1038/ki.2010.101. Epub 2010 Apr 14.
Nephron number varies widely between 0.3 and 1.3 million per kidney in humans. During fetal life, the rate of nephrogenesis is influenced by local retinoic acid (RA) level such that even moderate maternal vitamin A deficiency limits the final nephron number in rodents. Inactivation of genes in the RA pathway causes renal agenesis in mice; however, the impact of retinoids on human kidney development is unknown. To resolve this, we tested for associations between variants of genes involved in RA metabolism (ALDH1A2, CYP26A1, and CYP26B1) and kidney size among normal newborns. Homozygosity for a common (1 in 5) variant, rs7169289(G), within an Sp1 transcription factor motif of the ALDH1A2 gene, showed a significant 22% increase in newborn kidney volume when adjusted for body surface area. Infants bearing this allele had higher umbilical cord blood RA levels compared to those with homozygous wild-type ALDH1A2 rs7169289(A) alleles. Furthermore, the effect of the rs7169289(G) variant was evident in subgroups with or without a previously reported hypomorphic RET 1476(A) proto-oncogene allele that is critical in determining final nephron number. As maternal vitamin A deficiency is widespread in developing countries and may compromise availability of retinol for fetal RA synthesis, our study suggests that the ALDH1A2 rs7169289(G) variant might be protective for such individuals.
人类每个肾脏的肾单位数量在 0.3 到 130 万个之间变化很大。在胎儿期，肾发生的速度受局部视黄酸（RA）水平的影响，即使是中度的母体维生素 A 缺乏也会限制啮齿动物的最终肾单位数量。RA 途径中基因的失活会导致小鼠肾发育不全；然而，视黄醇对人类肾脏发育的影响尚不清楚。为了解决这个问题，我们在正常新生儿中测试了参与 RA 代谢的基因（ALDH1A2、CYP26A1 和 CYP26B1）变体与肾脏大小之间的关联。ALDH1A2 基因 Sp1 转录因子基序内常见（五分之一）的 rs7169289(G) 变体的纯合性，在调整体表面积后，新生儿肾脏体积增加了 22%。与具有纯合野生型 ALDH1A2 rs7169289(A)等位基因的婴儿相比，携带该等位基因的婴儿脐带血 RA 水平更高。此外，rs7169289(G) 变体的效应在先前报道的低效能 RET 1476(A)原癌基因等位基因的亚组中是明显的，该等位基因在确定最终肾单位数量方面至关重要。由于发展中国家普遍存在母体维生素 A 缺乏，并且可能会影响胎儿 RA 合成的视黄醇可用性，因此我们的研究表明，ALDH1A2 rs7169289(G) 变体可能对这些个体具有保护作用。
