3-nitrotyrosine and Nephrosclerosis

In this study we examined the short- and long-term impact of early life dietary sodium (Na) on prenatally programmed hypertension. Hypertension was induced in rat offspring by a maternal low protein (LP) diet. Control and LP offspring were randomized to a high (HS), standard (SS), or low (LS) Na diet after weaning. On the SS diet, the LP pups developed hypertension by 6 weeks of age. The development of hypertension was prevented by the LS diet and exacerbated by the HS diet. Kidney nitrotyrosine content, a measure of oxidative stress, was reduced by the LS diet compared with the HS diet. The modified diets had no effect on control pups. A group of animals on the SS diet was followed up to 51 weeks of age after an early life 3-week exposure to the HS or LS diet. This brief early exposure of LP animals to the LS diet prevented the later development of hypertension and ameliorated the nephrosclerosis observed after early exposure to the HS diet. The LP offspring with early exposure to LS diet had lost their salt-sensitivity when challenged with the HS diet at the age of 43-49 weeks. No effect of early life dietary Na was observed in control animals. These results show that hypertension in this model is salt sensitive and may, in part, be mediated by salt-induced renal oxidative stress and that there may exist a developmental window which allows postnatal "reprogramming" of the hypertension.

Topics: Animals; Blood Pressure; Diet, Protein-Restricted; Female; Hypertension; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Nephrosclerosis; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Sprague-Dawley; Sodium; Tyrosine

2,3-Dimercaptosuccinic acid (DMSA), a sulfhydryl-containing chelator, has previously been shown to reduce mean blood pressure in lead-treated rats. In the present study we have demonstrated that DMSA (0.5% for 5 days every 2 weeks) also reduces mean blood pressure in the Dahl salt-sensitive (SS) rat. Six-week-old Dahl SS and salt resistant (SR) rats were placed on a 0.3% NaCl diet for two weeks, followed by an 8% NaCl diet for four weeks. Eight SS and 8 SR rats remained untreated while 8 SS and 8 SR rats were treated with DMSA. DMSA treatment ameliorated the mean blood pressure rise in the Dahl SS rats (141 +/- 5 vs. 120 +/- 4 mm Hg at 6 weeks, P < 0.001). Nephrosclerosis was severe in untreated SS rats but absent in treated SS rats as well as in both treated and untreated SR rats. Reactive oxygen species formation, as assessed by kidney cortex content of malondialdehyde (MDA) and immunohistochemical demonstration of nitrotyrosine (a byproduct of peroxynitrite) in interlobular arteries, was increased in Dahl SS rats, but abolished by DMSA (MDA 9.65 +/- 0.33 nmol/g wet wt, untreated SS, vs. 6.46 +/- 0.51, treated SS, P < 0.001). The anti-nephrosclerotic action of DMSA was clearly disproportionate to the reduction in blood pressure. We conclude that the effect of DMSA was related instead to the reactive oxygen species scavenging properties of the thiol groups.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Chelating Agents; Chromatography, High Pressure Liquid; Immunohistochemistry; Male; Malondialdehyde; Nephrosclerosis; Oxidants; Rats; Rats, Inbred Strains; Reactive Oxygen Species; Renal Artery; Sodium, Dietary; Succimer; Tyrosine