Maternal nutrient restriction inhibits ureteric bud branching but does not affect the duration of nephrogenesis in rats

Abstract

Background: Maternal nutrient restriction produces offspring with fewer nephrons. We studied whether the reduced nephron number is due to the inhibition of ureteric branching or early cessation of nephrogenesis in rats. Signaling pathways involved in kidney development were also examined. Methods: The offspring of dams given food ad libitum (control (CON)) and those subjected to 50% food restriction (nutrient restriceted (NR)) were examined. results: At embryonic day 13 (E13), there was no difference between NR and CON in body weight or kidney size. Ureteric buds branched once in both NR and CON. At E14 and E15, body and kidney size were significantly reduced in NR. Ureteric bud tip numbers were also reduced to 50% of CON. On the other hand, the disappearance of nephrogenic zone and a nephron progenitor marker Cited1 was not different between CON and NR. The final glomerular number of NR was 80% of CON. Activated extracellular signal-regulated kinase (ERK), p38, PI3K, Akt, and mammallian target of rapamycin (mTOR), and protein expression of β-catenin were downregulated at E15. conclusion: Ureteric branching is inhibited and developmentally regulated signaling pathways are downregulated at an early stage by maternal nutrient restriction. These changes, not early cessation of nephrogenesis, may be a mechanism for the inhibited kidney growth and nephrogenesis. t he concept that disturbed intrauterine organogenesis affects the health and disease in the adulthood, termed developmental origins of health and disease, has been increasingly recognized. With respect to the kidney, low birth weight is associated with a risk for hypertension and renal disease, and reduced nephron number is considered to be the cause. In animals, maternal protein or global nutrient restriction, uterine artery ligation, hyperglycemia, and exposure to various agents such as glucocorticoids or alcohol produce offspring with fewer nephrons (1-6). Depletion of stem cells by increased apoptosis has been suggested to be responsible for the decreased nephron formation (1,3). On the other hand, ureteric bud branching is a fundamental step in determining nephron number. The mechanism of reduced nephron endowment in dexamethasone or ethanol exposure has been suggested to be inhibited branching morphogenesis in an organ culture study (5,7). Reduced ureteric branching has recently been reported in a model of maternal hyperglycemia in vivo (8).Another possible mechanism of reduced nephron number is early cessation of nephrogenesis. In human premature infants, nephrogenesis is reported to continue only up to 40 d after birth (9). These infants are under various stresses including hypoxia, infection, and medications adversely affecting nephrogenesis. It has been postulated that adverse conditions during development promote differentiation aiming at early maturation and survival at the expense of reduced organ growth. Newborn rats resemble human premature neonates in that nephrogenesis continues after birth. Early cessation of nephrogenesis, therefore, may b...

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

“…Maternal nutrient restriction significantly reduced fetal body weight and ureteric tip number at E14 in agreement with our previous report (Fig 1) [6]. Kidney surface area was not changed.…”

“…We hypothesized that the prevention of hypertension by FA could be through an effect on nephron number, which is known to be reduced by maternal low protein diet [1]. In our model of maternal nutrient restriction as well, nephron number was reduced along with the inhibited ureteric branching [6]. Since nutrients were reduced to 50% in our model, it is likely that the adverse effect on kidney development is through, at least in part, the deficiency of methyl donors including FA.…”

“…In animals, 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].…”

Shaping of the nephron – a complex, vulnerable, and poorly explored backdrop for noxae impairing nephrogenesis in the fetal human kidney

“…The cessation of nephrogenesis in the mouse changes gen activity in nephrogenic progenitor cells, lowers their number, and inhibits their proliferation [17]. Maternal nutrient restriction in rat reduces ureteric bud branching up to 50%, but surprisingly does not influence the duration of nephron formation [18]. A low protein diet alters the activity of gens in the mouse kidney by decreasing Slit2/Robo2 and Spry1, but stimulating Ret [19].…”

Mitogen-activated Protein Kinases in the Development of Normal and Diseased Kidneys

“…While low nephron number is thought to be the major cause, its mechanism has not been fully elucidated. We therefore investigated the mechanism in a rat model of maternal nutrient restriction 19) . We found that ureteric branching, an important determinant of nephron number, as well as kidney size was decreased by maternal nutrient restriction.…”