Metabolic programming during lactation stimulates renal Na+ transport in the adult offspring due to an early impact on local angiotensin II pathways

• Published in: PloS one 2011-07, Vol.6 (7), p.e21232
• Main Authors: Luzardo, Ricardo, Silva, Paulo A, Einicker-Lamas, Marcelo, Ortiz-Costa, Susana, do Carmo, Maria da Graça Tavares, Vieira-Filho, Leucio D, Paixão, Ana D O, Lara, Lucienne S, Vieyra, Adalberto
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin II; Angiotensin II - metabolism; Angiotensin II - pharmacology; Animals; Biological Transport - drug effects; Biology; Blood pressure; Blood Pressure - drug effects; Bowman's capsule; Cell Membrane - drug effects; Cell Membrane - metabolism; Collagen; Collagen - metabolism; Correlation analysis; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases - metabolism; Diet, Protein-Restricted - adverse effects; Eating - drug effects; Excretion; Female; Fish; Gene Expression Regulation, Enzymologic - drug effects; Glomerular filtration rate; Glomerular Filtration Rate - drug effects; Hypertension; In vivo methods and tests; Isoforms; Kidney - cytology; Kidney - drug effects; Kidney - metabolism; Kidney - physiology; Kidney Glomerulus - cytology; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Kidney Glomerulus - physiology; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - physiology; Kidneys; Kinases; Lactation; Lactation - metabolism; Male; Malnutrition; Malnutrition - etiology; Malnutrition - metabolism; Malnutrition - pathology; Malnutrition - physiopathology; Materials handling; Medicine; Medulla; Mothers; Na+/K+-exchanging ATPase; Nephrons; Offspring; Oncorhynchus mykiss; Ouabain; Pregnancy; Programming; Protein kinase C; Protein Kinase C - metabolism; Proteinuria; Proteinuria - etiology; Proteinuria - metabolism; Proximal tubules; Rats; Receptors; Receptors, Angiotensin - metabolism; Renal function; Rodents; Signal Transduction - drug effects; Signaling; Sodium; Sodium - metabolism; Sodium - urine; Sodium-Potassium-Exchanging ATPase - metabolism; Time Factors; Tubules; Undernutrition; Weaning
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021232

Several studies have correlated perinatal malnutrition with diseases in adulthood, giving support to the programming hypothesis. In this study, the effects of maternal undernutrition during lactation on renal Na(+)-transporters and on the local angiotensin II (Ang II) signaling cascade in rats were investigated. Female rats received a hypoproteic diet (8% protein) throughout lactation. Control and programmed offspring consumed a diet containing 20% protein after weaning. Programming caused a decrease in the number of nephrons (35%), in the area of the Bowman's capsule (30%) and the capillary tuft (30%), and increased collagen deposition in the cortex and medulla (by 175% and 700%, respectively). In programmed rats the expression of (Na(+)+K(+))ATPase in proximal tubules increased by 40%, but its activity was doubled owing to a threefold increase in affinity for K(+). Programming doubled the ouabain-insensitive Na(+)-ATPase activity with loss of its physiological response to Ang II, increased the expression of AT(1) and decreased the expression of AT(2) receptors), and caused a pronounced inhibition (90%) of protein kinase C activity with decrease in the expression of the α (24%) and ε (13%) isoforms. Activity and expression of cyclic AMP-dependent protein kinase decreased in the same proportion as the AT(2) receptors (30%). In vivo studies at 60 days revealed an increased glomerular filtration rate (GFR) (70%), increased Na(+) excretion (80%) and intense proteinuria (increase of 400% in protein excretion). Programmed rats, which had normal arterial pressure at 60 days, became hypertensive by 150 days. Maternal protein restriction during lactation results in alterations in GFR, renal Na(+) handling and in components of the Ang II-linked regulatory pathway of renal Na(+) reabsorption. At the molecular level, they provide a framework for understanding how metabolic programming of renal mechanisms contributes to the onset of hypertension in adulthood.