Long-Term Effects of Maternal Diabetes on Vascular Reactivity and Renal Function in Rat Male Offspring

Abstract

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 ...

Exposure to Maternal Diabetes Induces Salt-Sensitive Hypertension and Impairs Renal Function in Adult Rat Offspring

“…Interestingly, in inbred rat models of hypertension, the relationship between nephron number and blood pressure is still a matter of debate (24 -26). In addition, recently, Rocha et al (8) and Magaton et al (9) reported hypertension in rats issued from diabetic mothers without inborn nephron deficit. However, their model slightly differs from ours: 1) The level of maternal hyperglycemia is more pronounced in our model (we have previously shown that inborn nephron deficit correlated with the level of maternal hyperglycemia [13]); and 2) we performed direct glomerular counting with the gold-standard acid-maceration method, whereas they used an histological-derived method that is more appropriate to evaluate the density of glomeruli.…”

“…Together, these two sets of results seem to weight against a compensatory glomerular hypertrophy and hyperfiltration as factors of alteration and worsening of the renal function until 18 months of age. Concerning the study of Rocha et al (8), one must note that although decreased nephron number was not observed in young animals, the number of nephrons was reduced at 12 months in diabetic mother offspring rats. However, because no histological data were provided in their study to evaluate the extent of glomerulosclerosis, the mechanisms of ongoing nephron loss and its implication in the decline of renal function has not been elucidated in their model.…”

“…They include caudal regression syndrome and urogenital abnormalities, which can be as severe as renal agenesis (6). Besides these numerous epidemiological data concerning perinatal outcome of pregnancy of diabetic women, little is known about the long-term consequences of in utero exposure to maternal diabetes in adulthood (7)(8)(9).…”

The Influence of L-Arginine on Blood Pressure, Vascular Nitric Oxide and Renal Morphometry in the Offspring from Diabetic Mothers

“…In a previous study, we have demonstrated that maternal diabetes promotes remarkable changes in both kidney function and vascular reactivity in the mature offspring (15). Our data concerning diabetic offspring model (DO) pointed to an interesting model in which, although a normal nephron number was observed, two important factors-systemic hypertension and glomerular hypertrophy-which contribute to the progression of renal disease, were present.…”

“…No alteration in nephron number and in renal morphology was observed in the young offspring (15,29). In the study from Magaton et al (29), immunohistochemical analysis for antiproliferating cell nuclear antigen (PCNA), an index of growth rate, and for ␣-SM-actin, overexpressed during pathologic states, showed a similar pattern in both C and DO groups; these results confirm previous data from our group which indicate no renal morphologic changes in the young and adult offspring from diabetic mothers (15).…”