Prenatal programming of adult hypertension in the rat

Abstract

Background: Epidemiological studies have suggested that low birthweight is a risk factor for the development of essential hypertension in adulthood, but the mechanism is unknown. Methods: A rat model of intrauterine growth retardation was employed. Pregnant Sprague-Dawley rats were kept on 6% protein or on control isocaloric 20% protein diet from gestational day 12 until term. Systolic blood pressures of the offspring were monitored by the tail cuff method. Apoptosis was determined by the TUNEL method, cell proliferation by anti-Ki67 antibody, and the total number of glomeruli by the maceration method. Results are mean ± SD. Results: The kidney and body sizes of the offspring from the low-protein pregnancies (LP) were proportionately decreased at birth. Full catch-up growth occurred during the first two weeks of life. The kidneys were normal by standard histology but exhibited increased apoptosis without increased cell proliferation at eight weeks of age. The total number of glomeruli per kidney was decreased by 28% in males (P < 0.001) and by 29% in females (P < 0.01). By eight weeks of age, both male and female LP had systolic blood pressures that were 20 to 25 mm Hg higher than those of control animals (P < 0.001), and their 18-month survival was significantly decreased (44 vs. 93%, P < 0.01). During the prehypertensive stage, at four weeks of age, PRA in LP was low (1.7 ± 1.4 vs. 19.7 ± 5.5 ng/mL/hour in males, P < 0.0001; 4.9 ± 2.2 vs. 14.9 ± 7.2 ng/mL/hour in females, P < 0.0005), and aldosterone was high (93 ± 15 vs. 54 ± 27 pg/mL in males, P < 0.005; 93 ± 20 vs. 48 ± 20 pg/mL in females, P < 0.0001). Smaller but significant differences persisted at eight weeks of age. Conclusions: Adult blood pressure profile is susceptible to prenatal programming by maternal low-protein diet in the rat. The mechanism may involve an altered renin-aldosterone axis and a deficit in total nephron number.