Maternal Protein Restriction Suppresses the Newborn Renin-Angiotensin System and Programs Adult Hypertension in Rats

Abstract

Restriction of maternal protein intake during rat pregnancy produces offspring that are hypertensive in adulthood, but the mechanisms are not well understood. Our purpose was to determine whether this adult hypertension could be programmed during development by suppression of the fetal/newborn reninangiotensin system (RAS) and a consequent reduction in nephron number. Pregnant rats were fed a normal protein (19%, NP) or low-protein (8.5%, LP) diet throughout gestation. Birth weight was reduced by 13% (p Ͻ 0.0005), and the kidney/body weight ratio was reduced in LP pups. Renal renin mRNA levels were significantly reduced in newborn LP pups; renal renin concentration and renin immunostaining were suppressed. Renal tissue angiotensin II levels were also suppressed in newborn LP (0.079 Ϯ 0.002 ng/mg, LP versus 0.146 Ϯ 0.016 ng/mg, NP, p Ͻ 0.01). Mean arterial pressure in conscious, chronically instrumented adult offspring (21 wk) was higher in LP (135 Ϯ 1 mm Hg, LP versus 126 Ϯ 1 mm Hg, NP, p Ͻ 0.00007), and GFR normalized to kidney weight was reduced in LP (p Ͻ 0.04). The number of glomeruli per kidney was lower in adult LP offspring (21,567 Ϯ 1,694, LP versus 28,917 Ϯ 2,342, NP, p Ͻ 0.03), and individual glomerular volume was higher (1.81 Ϯ 0.16 10 6 m 3 , LP versus 1.11 Ϯ 0.10 10 6 m 3 , NP, p Ͻ 0.005); the total volume of all glomeruli per kidney was not significantly different. Thus, perinatal protein restriction in the rat suppresses the newborn intrarenal RAS and leads to a reduced number of glomeruli, glomerular enlargement, and hypertension in the adult. Abbreviations RAS, renin-angiotensin system ERPF, effective renal plasma flow NP, normal protein (19%) diet LP, low-protein (8.5%) diet ANGII, angiotensin II PAH, para-amino hippurate A decade ago, Barker et al. first reported an inverse relationship between birth weight and death from cardiovascular disease in adulthood (1). Subsequently, a number of epidemiologic studies in different parts of the world have found a relationship between early growth patterns and the risk of cardiovascular disease in adulthood (2-8). Although these findings remain somewhat controversial (9), the majority of evidence indicates that even within the "normal" range of birth weights, babies that are born smaller have a higher risk of death from cardiovascular disease when they reach adulthood. This indicates that some factor or factors in the perinatal environment, probably related at least in part to maternal nutrition, can "program" the individual for increased cardiovascular risk later in life. However, the precise physiologic and molecular mechanisms by which this programming occurs are unknown.Recently, a rat model of perinatal protein restriction has been identified that has several features in common with the observations in humans, suggesting that this may be a good animal model of the human condition. In particular, offspring ABSTRACT460

A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products

“…In addition, although there was an increase in mean glomerular volume in LPD offspring, there was no evidence to suggest that glomeruli were hyperfiltering. Indeed, the GFR per gram of kidney weight was reduced compared with NPD controls [35], possibly reflecting the 10 mmHg increase in mean arterial pressure in the LPD offspring.…”

“…In a carefully conducted stereological autopsy analysis of kidneys, Keller et al demonstrated that patients with primary hypertension had fewer glomeruli per kidney than their normotensive controls [34]. In addition, developmental nephron deficit and/or maternal protein restriction in rats has been linked to the development of adult onset hypertension [3,31,35]. However, consistent with our previous reports [5], in the present study there was no effect of maternal protein restriction (and thus reduced nephron endowment) on conscious mean arterial blood pressure in adulthood.…”

“…Hence, when adjusted for kidney weight, GFR was not significantly different in the LPD and NPD offspring and so there was no evidence to suggest glomerular hyperfiltration was occurring. Woods et al [33,35] have also investigated the effects of maternal protein restriction on renal function in adulthood in Sprague-Dawley rats. As in the present study, the LPD offspring had low birth weight and smaller kidneys with fewer glomeruli when compared with control NPD offspring.…”

Effect of Intrauterine Growth Restriction on Kidney Function at Young Adult Age: The Nord Trøndelag Health (HUNT 2) Study

“…Furthermore, the completeness of the perinatal registration enabled us to adjust BW for gestational age, which is considered important to obtain a valid measure of a subjects's exposure to IUGR. 7,[34][35][36] We found that IUGR was associated with low-normal kidney function in young adults from the general population. This is consistent with findings in subjects born very prematurely 17 .…”

“…Low kidney volume and nephron number were observed after IUGR in several animal models 6,7 and also in humans, newborns as well as adults, who died of nonrenal causes. [8][9][10] The clinical consequences of these alterations were investigated at different levels, and associations were found of IUGR with microalbuminuria, 11,12 faster progression of renal dysfunction in patients with specific kidney diseases, 13,14 and end-stage renal disease (ESRD).…”