Protein‐energy malnutrition during early gestation in sheep blunts fetal renal vascular and nephron development and compromises adult renal function

Abstract

Non-technical summaryA poor diet during pregnancy has been linked to long-term health outcomes for the baby, such as an increased risk of diseases of the heart and kidney. We show in an experimental model that recreates a poor diet during pregnancy, i.e. a diet low in protein with adequate energy, that kidney development in the baby is affected in such a way as to reduce the potential for new blood vessels to form. This results in a greater number of important, functional kidney cells spontaneously dying. Later in life, these effects in the kidney manifest as permanently reduced kidney function, especially if the baby subsequently becomes overweight as an adult. The research reinforces advice to pregnant mothers about the importance of eating a nutritionally balanced diet during pregnancy.AbstractA nutritionally poor maternal diet can reduce nephron endowment and pre-empt premature expression of markers for chronic renal disease in the offspring. A mechanistic pathway from variation in maternal diet through altered fetal renal development to compromised adult kidney structure and function with adult-onset obesity has not been described. We show that maternal protein-energy malnutrition in sheep blunts nephrogenic potential in the 0.44 gestation (65 days gestation, term ∼147 days) fetus by increasing apoptosis and decreasing angiogenesis in the nephrogenic zone, effects that were more marked in male fetuses. As adults, the low-protein-exposed sheep had reduced glomerular number and microvascular rarefaction in their kidneys compensated for, respectively, by glomerular hypertrophy and increased angiogenic support. In this study, the long-term mild anatomical deficits in the kidney would have remained asymptomatic in the lean state, but when superimposed on the broad metabolic challenge that obesity represents then microalbuminuria and blunted bilateral renal function revealed a long-term physiological compromise, that is only predicted to worsen with age. In conclusion, maternal protein-energy malnutrition specifically impacts fetal kidney vascular development and prevents full functionality of the adult kidney being achieved; these residual deficits are predicted to significantly increase the expected incidence of chronic kidney disease in prenatally undernourished individuals especially when coupled with a Western obesogenic environment.

Increased Leptin Response and Inhibition of Apoptosis in Thymocytes of Young Rats Offspring from Protein Deprived Dams during Lactation

“…It has been demonstrated that intrauterine growth restriction can induces apoptosis in fetal kidney and in beta cells of pups compromising the adult renal function and insulin secretion, respectively [52], [53]. Nevertheless, the maternal protein restriction during lactation had a protective effect on the thymocytes with lower spontaneously apoptosis rate, without altering the proliferative response.…”

Developmental Origins of Chronic Renal Disease: An Integrative Hypothesis

“…In rodent, despite strictly controlled conditions, the nephron endowment can vary by an average of 10% to 15% for a birth weight situated within normal range [122, 123]. Events that occur during the early stage of nephrogenesis can induce a nephron deficit without affecting birth weight [124–127]. Exposure to maternal low protein diet and administration of a short course of glucocorticoids during the early stage of nephrogenesis, in rodents (E14–17) and in sheep (E80), are sufficient to reduce nephron endowment (−20% to −40%) without inducing low birth weight [124–126].…”

LIM kinase function and renal growth: Potential role for LIM kinases in fetal programming of kidney development

“…The underlying causes are still to be fully established, but evidence points to developmental changes in organ systems which result in their limited functional capacity at maturity. Kidney development has been shown to be adversely impacted by maternal undernutrition during gestation with the result that offspring possess fewer nephrons than controls [6][7][8][9][10][11]. A reduced nephron complement has been strongly associated with a predisposition towards hypertension, coronary heart disease and renal disease [12][13][14] and animal studies have provided experimental support for these observations [6,15,16].…”