Fetal growth impairment can occur in pregnancy complicated by diabetes. Although several studies have focused the effects of nutritional status on intrauterine development, the long-term impact of maternal diabetes on vascular and renal function in the offspring is poorly investigated. In the present study, blood pressure profiles and renal function parameters were investigated in the offspring of diabetic rats (DO). Female rats were made diabetic throughout gestation with a single dose of streptozotocyn (STZ) 10 d before mating. After weaning, the offspring had free access to food and water. Arterial pressure was evaluated every 15 d. Functional and morphometric kidney studies were performed in newborn, 3, 6 and 12-mo-old male rats in DO and in controls, C. Although maternal diabetes did not affect nephron number in the young adult rat, glomerular hypertrophy developed from 3 mo on. Glomerular Filtration Rate and Renal Plasma Flow were observed to be significantly decreased in DO when compared with C, from 3 mo on. In DO, hypertension was observed from 8 wk on and persisted elevated throughout the experimental period (12 mo). Vascular reactivity, evaluated in mesenteric arterial bed showed a decreased endotheliumdependent vasodilatation in 12-mo-old DO animals, while preserved response to sodium nitroprusside was demonstrated. Our data show that exposure to intrauterine diabetes induced by STZ does not affect nephron number in the young offspring but can cause permanent changes in Nitric Oxide (NO)-related vascular response, which, in turn may accelerate the natural age-related nephron loss. Maternal status can affect several physiologic functions of the newborn. In addition, correlation between fetal growth conditions and susceptibility to a number of adult chronic diseases, including coronary heart disease, stroke and hypertension have been identified (1-4). Recently, we have demonstrated that maternal undernutrition promoted development of adult hypertension, impairment of the renal and endothelium functions, decreased absolute number of the nephrons and hypertrophy of the remaining glomeruli in the adult offspring (5-7). Although several experimental studies have focused the effects of the maternal undernutrition on fetal "programming" of adulthood disease, less attention has been paid to the possible in utero late effects of maternal diabetes. In fact, diabetes mellitus can impose several threats both to the mother and the offspring. Experimental and clinical studies have demonstrated that diabetic pregnancy increases the risk of intrauterine death, prematurity, perinatal mortality and congenital malformations (8 -12). Indeed, Chugh et al. (13) have demonstrated that a sustained exposure of the fetus to elevated concentration of glucose may result in diabetic embryopathy, which is characterized by a multitude of congenital birth defects, including those of the nervous, cardiovascular, skeletal, and renal systems. These malformations result from defects occurring in early organogenesis including failure of ...
Pregnant rats were subjected to 50% food restriction during the first or the second half of pregnancy, or throughout pregnancy. The effects of intrauterine food restriction, on kidney function and morphometry were studied in newborn and adult (3 months) offspring. No differences in glomerular diameter were observed in newborn restricted rats compared with controls. The number of glomeruli was significantly lower both in newborn and 3-month-old restricted rats. However, glomerular diameter was increased in 3-month-old rats, which suggests that hypertrophic stimuli were present. The medulla/cortex ratio increased in adult rats submitted to food restriction during pregnancy, a finding that agrees with the preserved sodium and acid excretion, and the normal osmolar and free water clearance observed in these groups. These results show that the reduction in glomerular number is still present 3 months after birth in the progeny of mothers submitted to severe food restriction during pregnancy, suggesting impairment of glomerulogenesis even after birth. Intra utero undernutrition can be regarded as an experimental model of glomerular hypertrophy.
Although several studies have focused on the effects of nutritional status during intrauterine development, few have addressed the impact of maternal diabetes mellitus on renal function and morphology in the young offspring. In the present study, renal morpho-functional aspects were studied in the offspring of diabetic rats. Diabetes was induced in female rats with a single dose of streptozotocyn (STZ), 10 days before mating. After weaning, the offspring (DO) had free access to food and water. Arterial blood pressure was measured, by tail plethysmography, from 2 months on. Renal function was evaluated in 2- and 3-month-old rats in the DO group and in controls (C). Analysis of renal morphology was carried out in newborn and in 1-, 2- and 3-month-old rats in both groups. Although the nephron number was not changed in the DO group, glomerular hypertrophy was observed from 2 months on. At the same age, the glomerular filtration rate was significantly reduced in DO, and blood pressure was significantly increased, when compared to C. Glucose tolerance test (GTT) from DO showed a different profile when compared to C. The number of PCNA positive cells in renal tissue was similar in both groups. Our data suggests that exposure to intrauterine diabetes may be an important cause of both impaired renal function and hypertension in offspring, without changes in the nephron number.
We have previously demonstrated that 3-month-old rats submitted to 50% intrauterine food restriction showed a decreased number of nephrons with increased glomerular diameter, a fact that suggests compensatory hypertrophy. In the present study, we extended the investigation and performed serial blood pressure measurements and renal function evaluation in 8- and 12-week-old rats submitted to 50% intrauterine food restriction (groups R8 and R12) and in age-matched control rats (groups C8 and C12). After weaning, six to eight animals from each group received oral supplements of 2% L-arginine ( L-arg) solution for 4 or 8 weeks (groups CA8, CA12, RA8, RA12). Our findings showed that mean blood pressure (MBP), which was significantly increased from 8 weeks on in R rats, markedly decreased after L-arg supplementation. In control animals, no alterations in MBP were observed with L-arg. Proteinuria was within normal limits in all groups studied but L-arg caused a significant decrease in this parameter in both the RA8 and RA12 groups. Glomerular filtration rate (GFR, ml/min per kg) was significantly decreased in the C8 control group (3.75+/-0.12) and in both restricted groups R8 and R12, (2.47+/-0.13 and 3.76+/-0.16, respectively) compared with the C12 group (6.09+/-0.31; P<0.05 for all comparisons). L-Arg caused an increase in GFR only in the younger groups, C8 and R8. In a separate set of experiments, acetylcholine (ACh)-induced relaxation was examined in mesenteric arteries. The R12 group showed a significant impairment of the response to ACh, which returned to normal values after L-arg supplementation. Urinary excretion of NO(x) (NO3- + NO2-) was significantly decreased in 8- and 12-week-old food-restricted rats relative to control rats. Our data indicate that, besides the known decrease in absolute nephron number, disturbances in the production/sensitivity to the L-arg-nitric oxide system may contribute to the early appearance of hypertension in the offspring of mothers submitted to significant food restriction.
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