Folic acid supplementation alleviates reduced ureteric branching, nephrogenesis, and global DNA methylation induced by maternal nutrient restriction in rat embryonic kidney.

Midori Awazu,Mariko Hida,Michael Bader

doi:10.1371/journal.pone.0230289

Abstract

We previously reported that maternal nutrient restriction (NR) inhibited ureteric branching, metanephric growth, and nephrogenesis in the rat. Here we examined whether folic acid, a methyl-group donor, rescues the inhibition of kidney development induced by NR and whether DNA methylation is involved in it. The offspring of dams given food ad libitum (CON) and those subjected to 50% food restriction (NR) were examined. NR significantly reduced ureteric tip number at embryonic day 14, which was attenuated by folic acid supplementation to nutrient restricted dams. At embryonic day 18, glomerular number, kidney weight, and global DNA methylation were reduced by NR, and maternal folic acid supplementation again alleviated them. Among DNA methyltransferases (DNMTs), DNMT1 was strongly expressed at embryonic day 15 in CON but was reduced in NR. In organ culture, an inhibitor of DNA methylation 5-aza-2 '-deoxycytidine as well as medium lacking methyl donors folic acid, choline, and methionine, significantly decreased ureteric tip number and kidney size mimicking the effect of NR. In conclusion, global DNA methylation is necessary for normal kidney development. Folic acid supplementation to nutrient restricted dams alleviated the impaired kidney development and DNA methylation in the offspring.

Highlights

It is well recognized that an adverse intrauterine environment affects the health and disease in the adulthood referred to as the developmental origins of health and disease (DOHaD) concept
We examined whether folic acid (FA) supplementation rescues kidney development inhibited by maternal nutrient restriction
Effect of folic acid supplementation on the reduction in body weight and ureteric tip number induced by maternal nutrient restriction at embryonic day 14

Summary

Introduction

It is well recognized that an adverse intrauterine environment affects the health and disease in the adulthood referred to as the developmental origins of health and disease (DOHaD) concept. With respect to the kidney, low birth weight is associated with a risk for hypertension and renal disease. Reduced nephron number has been linked to these associations. Maternal protein or global nutrient restriction, uterine artery ligation, and exposure to various agents such as glucocorticoids or alcohol produce offspring with fewer nephrons [1,2,3,4,5]. As a mechanism of reduced nephron endowment, we previously reported reduced ureteric bud branching in a rat model of maternal nutrient restriction [6].

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