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

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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.