Ana D.O. Paixão

Renal function in adult rats subjected to prenatal dexamethasone

1. Prenatal dexamethasone leads to low birth weight and compromises organogenesis, but its effects on nephrogenesis in male and female rats have not yet been investigated extensively. Reduced renal mass may be responsible for hypertension and renal haemodynamic and morphological adjustments to maintain the glomerular filtration rate (GFR). Subsequently, these compensatory mechanisms determine glomerular sclerosis and irreversible reduction in GFR. When a high‐protein diet is associated with reduced renal mass, it accelerates glomerular sclerosis and the decline in renal function. The aim of the present study was to evaluate whether rats subjected to prenatal dexamethasone and a high‐protein diet during growth present a premature decline in renal function.

Regional Brazilian Diet-Induced Low Birth Weight Is Correlated with Changes in Renal Hemodynamics and Glomerular Morphometry in Adult Age

Number of nephrons, renal hemodynamics, and glomerular morphometry were assessed in rats submitted to a multideficient diet which was developed from a basic regional diet consumed in a Brazilian region of sugarcane cultivation. We evaluated three groups of male Wistar rat offspring: (1) from dams fed a standard diet throughout mating, pregnancy and lactation (control group) and (2) from dams fed the multideficient diet during mating and pregnancy (MalN1 group) or (3) throughout mating, pregnancy, and lactation (MalN2 group). At adult age, the animals were anesthetized to measure mean arterial blood pressure and renal hemodynamics. The MalN1 group, as compared with the control group, showed unaltered body and kidney weights, nephron deficiency, a high mean arterial blood pressure, glomerular hypertrophy, and renal vasoconstriction. The MalN2 group showed the same nephron deficiency and mean arterial blood pressure levels as the MalN1 group. These animals exhibited lower body and kidney weights and no glomerular hypertrophy. In conclusion, the alterations induced by intrauterine malnutrition are compatible with the development of chronic renal failure.

Renal molecular mechanisms underlying altered Na + handling and genesis of hypertension during adulthood in prenatally undernourished rats

In the present study, we investigated the development of hypertension in prenatally undernourished adult rats, including the mechanisms that culminate in dysfunctions of molecular signalling in the kidney. Dams were fed a low-protein multideficient diet throughout gestation with or without α-tocopherol during lactation. The time course of hypertension development followed in male offspring was correlated with alterations in proximal tubule Na+-ATPase activity, expression of angiotensin II (Ang II) receptors, and activity of protein kinases C and A. After the establishment of hypertension, Ang II levels, cyclo-oxygenase 2 (COX-2) and NADPH oxidase subunit expression, lipid peroxidation and macrophage infiltration were examined in renal tissue. Lipid peroxidation in undernourished rats, which was very intense at 60 d, decreased at 90 d and returned to control values by 150 d. During the prehypertensive phase, prenatally undernourished rats exhibited elevated renal Na+-ATPase activity, type 2 Ang II receptor down-regulation and altered protein kinase A:protein kinase C ratio. Stable late hypertension coexisted with highly elevated levels of Ang II-positive cells in the cortical tubulointerstitium, enhanced increase in the expression of p47phox (NADPH oxidase regulatory subunit), marked down-regulation of COX-2 expression, expanded plasma volume and decreased creatinine clearance. These alterations were reduced when the dams were given α-tocopherol during lactation. The offspring of well-nourished dams treated with α-tocopherol exhibited most of the alterations encountered in the offspring of undernourished dams not treated with α-tocopherol. Thus, alterations in proximal tubule Na+ transport, subcellular signalling pathways and reactive oxygen species handling in renal tissue underpin the development of hypertension.

Low sodium chloride content in a multideficient diet induces renal vasodilatation in rats

The present study investigated malnutrition in rats fed a diet deficient in proteins, lipids, vitamins and minerals, including sodium chloride. The renal function of malnourished 3-month old Wistar rats, assigned from weaning to the multideficient diet, supplemented or not supplemented with sodium chloride was evaluated. Compared with standard diet fed rats the groups maintained on the multideficient diet, regardless of the sodium content, showed body weight reduced by at least 58% and higher urinary sodium excretion. The rats on the multideficient diet not supplemented with sodium chloride exhibited low renal vascular resistance and high renal blood flow. In contrast, the rats on the multideficient diet supplemented with sodium chloride failed to show alterations in either the renal vascular resistance or in the renal blood flow. Although severe, the malnutrition was characterized by a negative balance of sodium that might have contributed with the renal vasodilatation seen when the content of sodium was low in diet.

Repercussion of acetylsalicylic acid during fetal development on later renal hemodynamics of rats.

Acetylsalicylic acid (ASA) during pregnancy reaches the fetus. It seems important to know possible repercussions of ASA on later renal function of the offspring, as well as repercussions of this drug on factors that may influence fetal development, such as maternal plasma volume and placental oxidative stress. It was evaluated whether ASA changes maternal plasma volume and/or placental oxidative stress, fetal weight and renal function of the offspring at adult life. ASA (100 mg/kg/day, p.o., dissolved in ETOH 10%) or ETOH 10% was administered to Wistar rat dams, from the day 7 to day 20 of pregnancy/parturition. Plasma volume and the placental oxidative stress were evaluated on day 20 of pregnancy, using, respectively, the Evans blue dye and the thiobarbituric acid reactive substances methods. Mean arterial pressure, renal blood flow (RBF) and glomerular filtration rate (GFR) were evaluated in the anesthetized offspring, at the age of 90 days, using a blood pressure transducer, a flow probe and inulin clearance respectively. Plasma volume was 76% (P < 0.05) higher in ASA compared with that in control dams, but placental oxidative stress was the same for both groups. Fetal body weight, the number of nephrons, GFR, RBF and renal vascular resistance were similar for the same gender among the offspring of the two groups. However, reduced hematocrit (9.8%, P < 0.05), increased renal plasma flow (27%, P < 0.05) and reduced filtration fraction (32%, P < 0.05) were seen in the female offspring. In conclusion, although ASA had increased maternal plasma volume, it did not change nephrogenesis nor GFR in the adult offspring. The changes in renal plasma flow and filtration fraction seen in the ASA female offspring might partially be due to the reduced hematocrit.

Renal Effects of Essential Fatty Acid Deficiency in Hydropenic and Volume-Expanded Rats

The aim of this paper was to study the effects of essential fatty acid (EFA) on fractional sodium excretion (FENa+) and renal hemodynamics in rats during hydropenia (H) and acute volume expansion (VE), successively. Mean arterial pressure (MAP) and renal blood flow (RBF) were measured using a blood pressure transducer and a flow probe, respectively, both connected to a flowmeter. Glomerular filtration rate (GFR) was estimated by inulin clearance. The rats receiving coconut oil as only source of dietary lipids (the EFA-deficient group) presented lower levels of linoleic acid in cortex and medulla and lower body weight than the rats receiving soy oil in place of coconut oil (the control non-EFA-deficient group). During H, the EFA-deficient rats exhibited a lower level of renal vascular resistance resulting in a higher level of RBF and a higher urinary flow (V’) and FENa+, although GFR was lower than in the control group. During VE, the rats of the control group responded with increased MAP, RBF, V’ and FENa+, which were not found in the EFA-deficient group, suggesting an impaired hemodynamic adjustment in EFA deficiency. In conclusion, both experimental conditions revealed that EFA deficiency affects the renal hemodynamics.

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.

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.