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ABSTRACT: Sodium retention has been proposed as the cause of hypertension in the LP rat (offspring exposed to a maternal low-protein diet in utero) model of developmental programming because of increased renal NKCC2 (Na+/K+/2Cl- co-transporter 2) expression. However, we have shown that LP rats excrete more rather than less sodium than controls, leading us to hypothesize that LP rats ingest more salt in order to maintain sodium balance. Rats were fed on either a 9% (low) or 18% (control) protein diet during pregnancy; male and female offspring were studied at 4 weeks of age. LP rats of both sexes held in metabolism cages excreted more sodium and urine than controls. When given water to drink, LP rats drank more and ate more food than controls, hence sodium intake matched excretion. However, when given a choice between saline and water to drink, the total volume of fluid ingested by LP rats fell to control levels, but the volume of saline taken was significantly larger [3.8±0.1 compared with 8.8±1.3 ml/24 h per 100 g of body weight in control and LP rats respectively; P<0.001]. Interestingly food intake also fell to control levels. Total body sodium content and ECF (extracellular fluid) volumes were greater in LP rats. These results show that prenatal programming of renal sodium wasting leads to a compensatory increase in salt appetite in LP rats. We speculate that the need to maintain salt homoeostasis following malnutrition in utero stimulates greater food intake, leading to accelerated growth and raised BP (blood pressure).
Clinical Science 10/2011; 122(6):281-8. · 4.61 Impact Factor
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ABSTRACT: Hypertension and renal dysfunction can be programmed in the rat by prenatal exposure to a low-protein (LP) diet. Expression of the renal thick ascending limb (TAL) sodium transporter NKCC2 is up-regulated, which has been predicted to result in greater sodium reabsorption. However, we have shown that LP rats excrete more not less sodium. The aim of this study was to determine whether the increased abundance of sodium:potassium:chloride (Na(+):K(+):2Cl(-)) co-transporter (NKCC2) leads to enhanced sodium uptake by the TAL. Pregnant Wistar rats were fed a control (18%) or LP (9%) diet. Amiloride (AM), bendroflumethiazide (BF), and furosemide (FUR) were administered acutely to male offspring at 4 weeks of age. Fractional excretion of sodium (FE(Na)) was significantly greater in vehicle-infused LP rats (3.0 ± 0.3%) compared with controls (1.7 ± 0.5, P < 0.01). FE(Na) by the LP proximal tubule did not differ from controls, whereas FE(Na) by the distal tubule was significantly greater (P < 0.01). These differences were abolished by the administration of AM + BF (equivalent to the outflow from the TAL) and AM + BF + FUR (equivalent to the outflow from the proximal tubule), suggesting that the increase in NKCC2 expression was not functional. However, during acute salt loading, the LP rat pressure natriuresis curve was shifted rightward, implying that raised systemic blood pressure is required to match urinary sodium excretion with dietary intake. These data suggest that renal sodium handling is impaired in the LP rat but that this is not due to increased NKCC2 expression.
Pediatric Nephrology 08/2011; 27(2):285-93. · 2.52 Impact Factor
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ABSTRACT: To investigate T-cell functional molecules and inflammatory cytokines and to assess T-cell apoptosis in malnourished infants, 64 infants from undernourished women and 28 healthy control infants were recruited to the study. Malnourished infants showed a significant decrease in the levels of circulating IL-2 and IL-7 and increases in the levels of IL-1β, IL-6, IL-10 and TNF-α, as measured by flow cytometry. There was a significant reduction in the number of CD3(+) T cells and an increase in apoptotic T cells, which was associated with an up-regulation of CD95 and PD-1 expression on CD3(+) T cells in malnourished compared to control infants. Significant reductions were also observed in the phosphorylation of AKT and STAT5 and in the expression of CCR7 and CXCR4 receptors in malnourished children, and these reductions were associated with a significant reduction in T-cell migratory capacity to their ligands CCL21 and CXCL12, respectively, as measured using an in vitro chemotaxis assay. Taken together, these data suggest that lymphocytes from malnourished infants are short-lived and dysfunctional.
Immunobiology 03/2011; 216(3):309-15. · 3.20 Impact Factor
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ABSTRACT: Developmental programming of hypertension, induced by maternal protein restriction, is associated with enhanced urinary excretion of sodium and calcium in the rat. Although calcium and magnesium are reabsorbed via different pathways, renal calcium excretion often parallels magnesium output. Accordingly, the aim of the current study was to assess magnesium handling in rats exposed to a low-protein (LP) diet in utero. Wistar rats were fed a control (18%) or LP (9%) diet throughout pregnancy; offspring were weaned onto standard rat chow and studied at 4 weeks of age. Renal clearance measurements were made in both volume expanded and euvolaemic anaesthetised rats; 24-hour magnesium turnover was also assessed in conscious animals. Plasma and total body magnesium content were measured. Total (U(Mg)V) and fractional excretion (FE(Mg)) of magnesium did not differ between control and LP rats under any of the experimental conditions. Neither plasma nor total body magnesium content differed between control and LP rats. Thus the hypercalciuria of LP rats is not mirrored by an increase in renal magnesium excretion. These data suggest that renal magnesium handling is not affected by developmental programming.
Kidney and Blood Pressure Research 03/2010; 33(2):94-9. · 1.46 Impact Factor
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ABSTRACT: Maternal dietary protein restriction during pregnancy results in an increase in offspring blood pressure in the rat. The kidneys of the low protein (LP) rat have fewer nephrons, increased hemodynamic sensitivity to angiotensin II and lower glomerular filtration rate, suggesting altered activity of the renin-angiotensin system. Angiotensin II plays a role in nephrogenesis through the AT(1) and AT(2) receptor subtypes. The aim of this study was to determine expression levels of both subtypes during nephrogenesis. Pregnant Wistar rats were fed either a control 18% protein diet or a low 9% protein (LP) diet. A 35% reduction in nephron number (p < 0.05) associated with a 50% reduction in total glomerular volume (p < 0.001) was seen in LP rats. Renal AT(1) (p < 0.0001) and AT(2) (p < 0.0001) receptor protein expression were significantly lower in LP rats from E18 to day 10. AT(1) expression in LP rat kidneys tended to increase over time while AT(2) expression declined until day 10, when it began to increase again. Angiotensin II-regulated cell proliferation may be perturbed in the LP rat kidney during nephrogenesis which could contribute to the reduction in nephron number and the elevation in blood pressure observed in this model of programmed hypertension.
Kidney and Blood Pressure Research 01/2010; 33(4):251-9. · 1.46 Impact Factor
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ABSTRACT: We recently demonstrated that type I Interferon (IFN) rescues in vitro, human B-lymphocytes from apoptosis via PI3Kδ/Akt, Rho-A, NFκB and Bcl-2/BclXL. In the present study we extended our work to clarify, in vivo, the role of type I IFN signalling on the circulating and lymphoid organs homing lymphocytes.
Two groups of mice 13 in each were set: type I IFN signalling blocked mice injected with anti-IFNAR1 antagonist antibody (10 mg/kg body weight) once/day for up to 20 days, and control group were injected with vehicle alone.
Flow cytometry analysis to monitor the blood lymphocyte phenotype and proliferation have shown a significant decrease in CD45R/B220(+) [corrected] B cells, CD4(+) and CD8(+) T cells in treated animals. Furthermore, the proliferative capacities of these lymphocyte subsets were significantly decreased in treated animals compared to those of control mice. Marked reduction in the plasma levels of IL-2 and IL-7 (cytokines important for the development of T and B cells) but not of IL-6 or IL-10 was observed in treated mice and this may a cause for emergence decrease in B and T cell numbers. Immunohistochemical studies have further shown a marked reduction in the numbers of CD20(+) B cells in spleen and Peyer's patches and CD3(+) T cells in thymus of treated animals. Moreover, electron microscopy examinations have revealed a loss of lymphocytes with characteristic features of apoptosis.
Our data confirmed that the in vivo inhibition of type I IFN signaling induce decrease in the numbers and defective functions of circulating and lymphoid organs homing lymphocytes providing a strong evidence for the protective effects of type 1 IFNs (IFN-α/β) on B and T lymphocytes.
Cellular Physiology and Biochemistry 01/2010; 26(6):1029-40. · 2.86 Impact Factor
