Mechanism of impaired nephrogeneis in intrauterine growth retardation and development of treatment strategies.

肾单位数量少会增加慢性肾病的风险。肾单位数目由宫内环境决定。我们研究了母体营养限制导致大鼠肾单位数量减少和输尿管芽分支减少的机制，发现半胱氨酸蛋白酶caspase-3在其中起着重要作用。我们试图通过给予锂来增加肾单位的数量，锂是一种激活b-连环蛋白的试剂，b-连环蛋白是半胱天冬酶3下游的一种分子。我们研究了母体营养限制对大鼠胚胎肾脏全基因组DNA甲基化的影响。在肾脏发育中重要的营养限制导致的甲基化基因主要是那些对输尿管分支至关重要的基因。靶向DNA甲基化可能会导致一种新的治疗策略。

Low nephron number increases the risk of chronic kidney disease. Nephron number is determined by intrauterine environment. We studied the mechanisms of low nephron number and reduced ureteric bud branching by maternal nutrient restriction in rats, and found that caspase-3, a cysteine protease, is playing an important role. We attempted to increase nephron number by giving lithium, an agent to activate b-catenin, a molecule downstream of caspase-3. Due to toxicity, however, this approach turned out to be unsuccessful.We investigated the effects of maternal nutrient restriction on genome-wide DNA methylation in rat embryonic kidney. Methylated genes by nutrient restriction important in kidney development are mostly those critical for ureteric branching. Targeting DNA methylation could lead to a new therapeutic strategy.