Maternal protein restriction leads to hyperresponsiveness to stress and salt-sensitive hypertension in male offspring

Abstract

Low birth weight humans often exhibit hypertension during adulthood. Studying the offspring of rat dams fed a maternal low-protein diet is one model frequently used to study the mechanisms of low birth weight-related hypertension. It remains unclear whether this model replicates key clinical findings of hypertension and increased blood pressure responsiveness to stress or high-salt diet. We measured blood pressure via radiotelemetry in 13-wk-old male offspring of maternal normal- and low-protein dams. Neither group exhibited hypertension at baseline; however, 1 h of restraint was accompanied by a significantly greater blood pressure response in low-protein compared with normal-protein offspring. To enhance the effect of a high-salt diet on blood pressure, normal- and low-protein offspring underwent right uninephrectomy, while controls underwent sham surgery. After 5 weeks on a high-salt diet (4% NaCl), mean arterial pressure in the Low-Protein+Sham offspring was elevated by 6 +/- 2 mmHg (P < 0.05 vs. baseline), while it remained unchanged in the normal-protein offspring. In the two uninephrectomized groups, blood pressure increased further, but was of similar magnitude. Glomerular filtration rate in the low-protein uninephrectomized offspring was 50% less than that in normal-protein offspring with intact kidneys. These data indicate that, while male low-protein offspring are not hypertensive during young adulthood, their blood pressure is hyperresponsive to restraint stress and is salt sensitive, and their glomerular filtration rate is more sensitive to hypertension-causing insults. Collectively, these may predispose for the development of hypertension later in life.

Fig. 1.

Time line for protocols 1 and 2. Transmitter refers to implant of radiotransmitter. High-salt diet was 4% NaCl. W, week(s); BP, blood pressure; Uni-NPX, uninephrectomy.

Fig. 2.

Baseline systolic, mean, and diastolic arterial pressure (top) and heart rate (bottom) measured with radiotelemetry in normal-protein (Norm. Prot.; ■, n = 11) and low-protein (Low Prot.; ○, n = 11) offspring. Data were collected over 4 consecutive days and are averaged every 12 h to display the daytime (D) and nighttime (N) variation in arterial pressure and heart rate. No significant differences were detected.

Fig. 3.

Change in mean arterial pressure and heart rate from baseline during 1 h of restraint stress in normal-protein (n = 6) and low-protein (n = 11) offspring. Note that the change in mean arterial pressure and heart rate in the low-protein offspring was significantly higher compared with the normal-protein offspring. Black bar, time period of restraint stress. *P < 0.05 vs. Norm. Prot.

Fig. 4.

Mean arterial pressure at baseline and then during the 5th week on high-salt (4% NaCl diet) in normal protein+sham nephrectomy (Norm. Prot.+Sham NPX; black bar, n = 6); low protein+sham nephrectomy (Low Prot.+Sham NPX; white bar, n = 9); normal protein+uninephrectomy (Norm. Prot.+Uni-NPX, gray bar, n = 6); and low protein+uninephrectomy, (Low Prot.+Uni-NPX, hatched bar, n = 6). Note that mean arterial pressure in the Low Prot. group was salt sensitive and that uninephrectomy exacerbated salt sensitivity in both uninephrectomized groups to a similar degree. *P < 0.05 vs. baseline; †P < 0.05 vs. both Norm. and Low Prot.

Fig. 5.

Glomerular filtration rate normalized to body weight (top) and kidney (Kid.) weight (bottom) following 5 wk of high-salt diet in Norm. Prot.+Sham (black bar, n = 6), Low Prot.+Sham (white bar, n = 6), Norm. Prot.+Uni-NPX (gray bar, n = 4), and Low Prot.+Uni-NPX (hatched bar, n = 6). Note that glomerular filtration rate in the Low Prot.+Uni-NPX group was ∼50% lower than that seen in the other groups. *P < 0.05 vs. Norm. Prot.+Sham NPX; †P < 0.05 vs. Low Prot.+Sham NPX.