L-Arginine supplementation improves insulin sensitivity and beta cell function in the offspring of diabetic rats through AKT and PDX-1 activation.

Maternal hyperglycemia can result in defects in glucose metabolism and pancreatic ß-cell function in offspring. The purpose of this study was to evaluate the impact of maternal diabetes mellitus on pancreatic islets, muscle and adipose tissue of the offspring, with or without oral l-Arginine supplementation. The induction of diabetes was performed using streptozotocin (60mg/kg). Animals were studied at 3 months of age and treatment (sucrose or l-Arginine) was administered from weaning. We observed that l-Arg improved insulin sensitivity in the offspring of diabetic mothers (DA), reflected by higher insulin-induced phosphorylation of Akt in muscle and adipose tissue. Insulin resistance is associated with increased oxidative stress and the NADPH oxidase enzyme plays an important role. Our results showed that the augmented interaction of p47PHOX with gp91PHOX subunits of the enzyme in skeletal muscle tissue in the offspring of diabetic rats (DV) was abolished after l-Arg treatment in DA rats. Maternal diabetes caused alterations in the islet functionality of the offspring leading to increased insulin secretion at both low (2.8mM) and high (16.7mM) concentrations of glucose. l-Arg reverses this effect, suggesting that it may be an important modulator in the insulin secretory process. In addition it is possible that l-Arg exerts its effects directly onto essential molecules for the maintenance and survival of pancreatic islets, decreasing protein expression of p47PHOX while increasing Akt phosphorylation and PDX-1 expression. The mechanism by which l-Arg exerts its beneficial effects may involve nitric oxide bioavailability since treatment restored NO levels in the pancreas.

Influence of birth weight on the renal development and kidney diseases in adulthood: experimental and clinical evidence.

Several clinical and experimental studies support the hypothesis that foetal programming is an important determinant of nephropathy, hypertension, coronary heart disease, and type 2 diabetes during adulthood. In this paper, the renal repercussions of foetal programming are emphasised, and the physiopathological mechanisms are discussed. The programming of renal diseases is detailed based on the findings of kidney development and functional parameters.

Micronutrient prenatal supplementation prevents the development of hypertension and vascular endothelial damage induced by intrauterine malnutrition.

AIMS: The premise that intrauterine malnutrition plays an important role in the development of cardiovascular and renal diseases implies that these disorders can be programmed during fetal life. Here, we analyzed the hypothesis that supplementation with mixed antioxidant vitamins and essential mineral in early life could prevent later elevation of blood pressure and vascular and renal dysfunction associated with intrauterine malnutrition. MAIN METHODS: For this, female Wistar rats were randomly divided into three groups on day 1 of pregnancy: control fed standard chow ad libitum; restricted group fed 50% of the ad libitum intake and a restricted plus micronutrient cocktail group treated daily with a combination of micronutrient (selenium, folate, vitamin C and vitamin E) by oral gavage. KEY FINDINGS: In adult offspring, renal function and glomerular number were impaired by intrauterine malnutrition, and the prenatal micronutrient treatment did not prevent it. However, increased blood pressure and reduced endothelium-dependent vasodilation were prevented by the micronutrient prenatal treatment. Intrauterine malnutrition also led to reduced NO production associated with increased superoxide generation, and these parameters were fully normalized by this prenatal treatment. SIGNIFICANCE: Our current findings indicate that programming alterations during fetal life can be prevented by interventions during the prenatal period, and that disturbance in availability of both antioxidant vitamins and mineral may play a crucial role in determining the occurrence of long-term cardiovascular injury.

Effect of sodium overload on renal function of offspring from diabetic mothers.

The aim if this study was to evaluate the effect of sodium overload on blood pressure and renal function in the offspring of diabetic rat mothers. Diabetes was induced with a single dose of streptozotocin before mating. Experimental groups were control (C), offspring from diabetic mother (D), control with sodium chloride (NaCl) overload (CS), and offspring from diabetic mother submitted to NaCl overload (DS). After weaning, all groups received food ad libitum; groups C and D had water ad libitum, and CS and DS received NaCl 0.15 M as drinking water. Renal morphology and function were evaluated in 3-month-old rats. Glomerular area, macrophage infiltration, interlobular artery wall thickness, and renal vascular resistance were significantly increased in CS, D, and DS compared with C. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were decreased in CS and D compared with C. In DS, GFR and fractional filtration were increased, suggesting a state of hyperfiltration. Hypertension was observed in groups D, CS, and DS from 2 months on and was more severe in DS. Our data suggest that diabetes during intrauterine development and salt overload beginning at an early age can cause hypertension and renal injury. When these conditions were associated, morphological and functional changes were much more intense, suggesting acceleration in the process of kidney injury.

Brief and long maternal separations decrease corticosterone secretion in a lupus-prone strain: dissociation from disease-related parameters.

Neonatal manipulations are known to alter the activity of the immune system and the hypothalamus-pituitary-adrenal (HPA) axis. This study was performed in order to examine whether brief and long maternal separations (BMS and LMS, respectively) interfere with the onset and development of murine lupus in NZB/NZWF1 females, and to determine whether the pattern of corticosterone (CORT) secretion throughout life is associated to the expression of the disease. Maternal separation was performed daily during postnatal days 1-14, lasting 15 min in the BMS group and 3h in the LMS group. Blood was sampled from the retro-orbital plexus on the 9th week, and every other week, from 10th to 34th weeks of life, for detection of anti-nuclear antibodies (ANA) and anti-double-strand DNA (anti-dsDNA) antibodies, and for determination of CORT serum levels. Urine samples were collected on the 21st, 27th, 33rd and 37th weeks of life. There were no group differences in regard to disease-related parameters, but LMS females presented a tendency for late onset of anti-dsDNA antibodies. BMS and LMS mice exhibited reduced CORT levels compared to non-manipulated (NM) animals. There was a strong negative correlation between total mean CORT concentration and onset of ANA, and a strong positive correlation between total mean CORT concentration and life span only in the NM group. Neonatal manipulations appeared to eliminate these correlations; hence, both BMS and LMS modified basal CORT secretion and the association between glucocorticoids and immune activity in the NZB/NZWF1 mouse strain.

The influence of L-arginine on blood pressure, vascular nitric oxide and renal morphometry in the offspring from diabetic mothers.

The present study was designed to evaluate the effects of L-arginine (L-arg) supplementation on blood pressure, vascular nitric oxide content, and renal morphometry in the adult offspring from diabetic mothers. Diabetes mellitus was induced in female rats with a single dose of streptozotocin (50 mg/kg), before mating. The offspring was divided into four groups: group C (controls); group DO (diabetic offspring); group CA (controls receiving 2% L-arg solution dissolved in 2% sucrose in the drinking water) and group DA (DO receiving the L-arg solution). Oral supplementation began after weaning and continued until the end of the experiments. In DO, hypertension was observed, from 3 mo on. In DA, pressure levels were not different from C and CA. In 6-mo-old animals, basal NO production (assessed by DAF-2) was significantly depressed in DO in comparison to controls. The NO production was significantly increased after stimulation with Ach or BK in all groups, the increase being greater in control than in DO rats. L-arg was able to improve the NO production and to prevent the glomerular hypertrophy in the DO. Our data suggest that the bioavailability of NO is reduced in the DO, because L-arg corrected both the hypertension and glomerular hypertrophy.

Maternal diabetes mellitus--early consequences for the offspring.

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.

Long-term effects of maternal diabetes on vascular reactivity and renal function in rat male offspring.

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 endothelium-dependent 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.

Effects of intrauterine food restriction and long-term dietary supplementation with L-arginine on age-related changes in renal function and structure of rats.

We have previously demonstrated that restricting intrauterine food by 50% in 3-mo-old rats produced lower nephron numbers and early-onset hypertension, the latter being normalized by L-arginine administration. In 18-mo-old rats, such restriction increased glomerulosclerosis. In this study, we expanded our investigation, evaluating functional, morphologic, and immunohistochemical parameters in intrauterine-food-restricted 18-mo-old rats, either receiving L-arginine (RA18) or not (R18). Age-matched, non-food-restricted controls were assigned to similar groups with L-arginine (CA18) and without (C18). After weaning, L-arginine was given daily for 17 mo. No functional or morphologic changes were observed in C18 rats. The R18 rats developed early-onset hypertension, which persisted throughout the observation period, as well as significant proteinuria from 12 mo on. In RA18 rats, L-arginine decreased both blood pressure levels and proteinuria, and glomerular diameter was significantly smaller than in R18 rats (115.63 +/- 2.2 versus 134.8 +/- 1.0 mum, p < 0.05). However, in RA18 rats, glomerular filtration rate remained depressed. Although L-arginine prevented glomerulosclerosis (R18 = 14%, RA18 = 4%; p < 0.05), glomerular expression of fibronectin and desmin was still greater in RA18 rats than in controls. Our data show that, although L-arginine prevented hypertension and proteinuria, glomerular injury still occurred, suggesting that intrauterine food restriction may be one of the leading causes of impaired renal function in adult life.

Intrauterine undernutrition--renal and vascular origin of hypertension.

OBJECTIVE: A large number of clinical and experimental studies supports the hypothesis that intrauterine undernutrition is an important determinant of hypertension, coronary heart disease and non-insulin-dependent diabetes in the adult offspring. In this review, the renal and vascular repercussions of maternal undernutrition are emphasized, and the physiopatologic mechanisms discussed. The origin of hypertension is detailed based upon the findings of kidney functional parameters and endothelium function studies. A working model linking hypertension to intrauterine undernutrition is proposed.