Alpha-Tocopherol during lactation and after weaning alters the programming effect of prenatal high salt intake on cardiac and renal functions of adult male offspring.

Maternal salt overload programs cardiovascular and renal alterations in the offspring. However, beneficial and harmful effects of high dose vitamin E supplementation have been described in humans and animals. We investigated the hypothesis as to whether cardiac and renal alterations can be programmed by gestational salt overload, and can become further modified during lactation and after weaning. Male Wistar rats were used, being the offspring of mothers that drank either tap water or 0.3 mol/L NaCl for 20 days before and during pregnancy. α-Tocopherol (0.35 g/kg) was administered to mothers daily during lactation or to their offspring for 3 weeks post-weaning. Systolic blood pressure (tcSBP) was measured in juvenile rats aged 210 days. The response of mean arterial pressure (MAP) and heart rate (HR) to intravenous infusion of angiotensin II (Ang II) was also examined. Left ventricle plasma membrane (PMCA) and sarcoplasmic reticulum Ca2+ -ATPase (SERCA) activities, and certain parameters of renal function, were measured. Maternal saline programmed for increased body mass and kidney mass/body mass ratio, increased tcSBP, increased mean arterial pressure and heart rate with anomalous response to infused Ang II. In the heart, saline increased PMCA and α-Tocopherol per se increased PMCA/SERCA. In the kidney, the most remarkable result was the silent saline programming of CrCl , which was sensitized for a sharp decrease after α-Tocopherol. In conclusion, the combination of maternal saline overload and high α-Tocopherol immediately after birth leads to simultaneous cardiovascular and renal alterations in the young offspring, like those encountered in type V cardiorenal syndrome.

Oxidative stress induced by prenatal LPS leads to endothelial dysfunction and renal haemodynamic changes through angiotensin II/NADPH oxidase pathway: Prevention by early treatment with α-tocopherol.

We investigated whether hypertension induced by maternal lipopolysaccharide (LPS) administration during gestation is linked to peripheral vascular and renal hemodynamic regulation, through angiotensin II → NADPH-oxidase signalling, and whether these changes are directly linked to intrauterine oxidative stress. Female Wistar rats were submitted to LPS, in the absence or presence of α-tocopherol during pregnancy. Malondialdehyde in placenta and in livers from dams and foetuses was enhanced by LPS. Tail-cuff systolic blood pressure (tcSBP) was elevated in the 16-week-old LPS offspring. Renal malondialdeyde and protein expression of NADPH oxidase isoform 2 were elevated in these animals at 20 weeks of age. Maternal α-tocopherol treatment prevented the elevation in malondialdehyde induced by LPS on placenta and livers from dams and foetuses, as well as prevented the elevation in tcSBP and the elevation in renal malondialdehyde in adult life. LPS offspring presented impairment of endothelium-dependent relaxation in aorta and mesenteric rings, which was blunted by angiotensin type 1 receptor (AT1R) blockade and NADPH oxidase inhibition. At age of 32 weeks, renal hemodynamic parameters were unchanged in anaesthetised LPS offspring, but angiotensin II infusion led to an increased glomerular filtration rate paralleled by filtration fraction elevation. The renal haemodynamic changes provoked by angiotensin II was prevented by early treatment with α-tocopherol and by late treatment with NADPH oxidase inhibitor. These results point to oxidative stress as a mediator of offspring hypertension programmed by maternal inflammation and to the angiotensin II → NADPH oxidase signalling pathway as accountable for vascular and renal dysfunctions that starts and maintains hypertension.

Perinatal α-tocopherol overload programs alterations in kidney development and renal angiotensin II signaling pathways at birth and at juvenile age: Mechanisms underlying the development of elevated blood pressure.

α-Tocopherol (α-Toc) overload increases the risk of dying in humans (E.R. Miller III et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality Ann Int Med. 142 (2005) 37-46), and overload during early development leads to elevation of blood pressure at adult life, but the mechanism(s) remains unknown. We hypothesized that α-Toc overload during organogenesis affects the renal renin angiotensin system (RAS) components and renal Na+ handling, culminating with late elevated blood pressure. Pregnant Wistar rats received α-Toc or the superoxide dismutase mimetic tempol throughout pregnancy. We evaluated components of the intrarenal renin angiotensin system in neonate and juvenile offspring: Ang II-positive cells, Ang II receptors (AT1 and AT2), linked protein kinases, O2- production, NADPH oxidase abundance, lipid peroxidation and activity of Na+-transporting ATPases. In juvenile offspring we followed the evolution of arterial blood pressure. Neonates from α-Toc and tempol mothers presented with accentuated retardment in tubular development, pronounced decrease in glomerular Ang II-positive cells and AT1/AT2 ratio, intense production of O2- and upregulation of the α, ε and λ PKC isoforms. α-Toc decreased or augmented the abundance of renal (Na++K+)ATPase depending on the age and α-Toc dose. In juvenile rats the number of Ang II-positive cells returned to control values as well as PKCα, but co-existing with marked upregulation in the activity of (Na++K+) and Na+-ATPase and elevated arterial pressure at 30 days. We conclude that the mechanisms of these alterations rely on selective targeting of renal RAS components through genic and pro-oxidant effects of the vitamin.

Bioactive lipids are altered in the kidney of chronic undernourished rats: is there any correlation with the progression of prevalent nephropathies?

BACKGROUND: Undernutrition during childhood leads to chronic diseases in adult life including hypertension, diabetes and chronic kidney disease. Here we explore the hypothesis that physiological alterations in the bioactive lipids pattern within kidney tissue might be involved in the progression of chronic kidney disease. METHODS: Membrane fractions from kidney homogenates of undernourished rats (RBD) were submitted to lipid extraction and analysis by thin layer chromatography and cholesterol determination. RESULTS: Kidneys from RBD rats had 25% lower cholesterol content, which disturb membrane microdomains, affecting Ca2+ homeostasis and the enzymes responsible for important lipid mediators such as phosphatidylinositol-4 kinase, sphingosine kinase, diacylglicerol kinase and phospholipase A2. We observed a decrease in phosphatidylinositol(4)-phosphate (8.8 ± 0.9 vs. 3.6 ± 0.7 pmol.mg-1.mim-1), and an increase in phosphatidic acid (2.2 ± 0.8 vs. 3.8 ± 1.3 pmol.mg-1.mim-1), being these lipid mediators involved in the regulation of key renal functions. Ceramide levels are augmented in kidney tissue from RBD rats (18.7 ± 1.4 vs. 21.7 ± 1.5 fmol.mg-1.min-1) indicating an ongoing renal lesion. CONCLUSION: Results point to an imbalance in the bioactive lipid generation with further consequences to key events related to kidney function, thus contributing to the establishment of chronic kidney disease.

Maternal Na+ intake induces renal function injury in rats prevented by a short-term angiotensin converting enzyme inhibitor.

The Na+ -ATPase, a secondary pump in the proximal tubule, is only weakly responsive to angiotensin II in adult offspring exposed perinatally to high Na+ intake. We have investigated whether the offspring from mothers given 0.3 mol/L NaCl show an ineffective angiotensin II action to increase in blood pressure. It was hypothesized that functional alterations at adult life are associated with the number of angiotensin II-positive cells in the developing kidney, with increased oxidative stress in maternal/foetal organs, or with morphometrical changes in placentas. Wistar female rats were maintained on 0.3 mol/L NaCl in their drinking water from 20 days before conception until weaning. After weaning, some of the male offspring were treated with enalapril for 21 days. Glomerular filtration rate was recorded up to 210 days of age, when mean arterial pressure was measured after infusion of angiotensin II. To investigate the placenta and foetal kidneys, mothers on tap water or NaCl were also treated with alpha-tocopherol, pregnancy being interrupted on the 20th day. There were no changes in the number of cells positive for angiotensin II in the foetal kidney and unchanged lipid peroxidation in the placenta of offspring exposed to NaCl, but the intermediate trophoblast area in the junctional zone was increased, possibly reducing maternal-foetal exchange. Glomerular filtration rate was reduced and there was an attenuated effect of angiotensin II on elevation of blood pressure, which could be mediated by an elevated angiotensin II during early life, once these disturbances had been prevented by early and short-term treatment with enalapril.

Mechanisms involving Ang II and MAPK/ERK1/2 signaling pathways underlie cardiac and renal alterations during chronic undernutrition.

BACKGROUND: Several studies have correlated protein restriction associated with other nutritional deficiencies with the development of cardiovascular and renal diseases. The driving hypothesis for this study was that Ang II signaling pathways in the heart and kidney are affected by chronic protein, mineral and vitamin restriction. METHODOLOGY/PRINCIPAL FINDINGS: Wistar rats aged 90 days were fed from weaning with either a control or a deficient diet that mimics those used in impoverished regions worldwide. Such restriction simultaneously increased ouabain-insensitive Na+-ATPase and decreased (Na++K+)ATPase activity in the same proportion in cardiomyocytes and proximal tubule cells. Type 1 angiotensin II receptor (AT1R) was downregulated by that restriction in both organs, whereas AT2R decreased only in the kidney. The PKC/PKA ratio increased in both tissues and returned to normal values in rats receiving Losartan daily from weaning. Inhibition of the MAPK pathway restored Na+-ATPase activity in both organs. The undernourished rats presented expanded plasma volume, increased heart rate, cardiac hypertrophy, and elevated systolic pressure, which also returned to control levels with Losartan. Such restriction led to electrical cardiac remodeling represented by prolonged ventricular repolarization parameters, induced triggered activity, early after-depolarization and delayed after-depolarization, which were also prevented by Losartan. CONCLUSION/SIGNIFICANCE: The mechanisms responsible for these alterations are underpinned by an imbalance in the PKC- and PKA-mediated pathways, with participation of angiotensin receptors and by activation of the MAPK/ERK1/2 pathway. These cellular and molecular alterations culminate in cardiac electric remodeling and in the onset of hypertension in adulthood.