Abstract
BackgroundSeveral 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 FindingsWistar 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/SignificanceThe 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.
Highlights
Chronic undernutrition is a worldwide public health problem, especially in developing countries [1], where young people are vulnerable to the consequences of food restriction, including the development of different diseases in later life [2]
The animals were divided into four groups: (i) control (CTR) rats, with free access to standard chow (Purina Agribands) and water from weaning (21 days after birth) to 90 days of age; (ii) rats chronically subjected to the basic regional diet (BRD), with free access to the deficient diet and water from weaning to 90 days of age; (iii) CTR Los, control rats receiving Los (Merck) by gavage (30 mg/kg body mass) from weaning (21 days after birth) to 90 days of age; and (iv) BRD Los, BRD rats receiving the same treatment with Los
General data Dietary restriction led to an accentuated decrease in the rate of body weight gain in both the BRD and BRD Los groups compared with the CTR- and CTR Los-matched groups
Summary
Chronic undernutrition (with severe protein restriction) is a worldwide public health problem, especially in developing countries [1], where young people are vulnerable to the consequences of food restriction, including the development of different diseases in later life (adulthood) [2]. Chronic undernutrition provoked by protein restriction associated with other dietary deficiencies is not confined to early life; it is a widespread lifelong condition frequently imposed from conception, persisting through growth and development into adult life [9]. Some epidemiological studies have indicated a low incidence of hypertension under conditions of chronic undernutrition [13], [14]; but the opposite trend was found in other studies [15]. These differences could be ascribed to the differing proportions of nutrients in deficient diets. 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
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