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.

Chronic undernutrition alters renal active Na+ transport in young rats: potential hidden basis for pathophysiological alterations in adulthood?

BACKGROUND: Epidemiological studies in the northeastern region of Brazil show an association between hypertension and malnutrition, especially in areas where protein-deficient diets are combined with high salt intake. AIMS OF STUDY: We studied the consequences of a widely consumed deficient diet (basic regional diet, BRD), combined with high NaCl, on growth, renal Na+ and water handling and activities of ATP-dependent Na+ transporters in kidney proximal tubules. METHODS: Young rats were fed after weaning with a low-protein and high-salt diet, which mimics that used in a vast region of Brazil. Body mass was evaluated from weaning up to the 19th week of age. Glomerular filtration rate, proximal Na+ reabsorption, distal Na+ delivery, urinary excretion of Na+ and water, and urine concentration capacity were evaluated from serum and urine concentrations of creatinine, Na+ and Li+, and by measurement of urinary volume and density. The (Na+ + K+)ATPase and the ouabain-insensitive Na+-ATPase were studied in vitro by measuring ATP hydrolysis. Expression of (Na+ + K+)ATPase was evaluated by immunodetection with the use of a specific antibody anti alpha1-catalytic subunit isoform. RESULTS: Undernourished rats reached early adulthood (14 weeks) with body and renal masses that were 2.3 times lower than controls. These rats became hypertensive (mean arterial pressure 18.7 +/- 0.6 kPa vs 15.5 +/- 0.9 kPa in control group) and showed augmented fractional proximal Na+ reabsorption (61.0 +/- 0.3% vs 81.8 +/- 2.2%) with a concomitant decrease in distal Na+ delivery (9.5 +/- 0.5 micromol/min vs 14.0 +/- 0.2 micromol/min per 100 g body weight). Urinary Na+ excretion was higher in BRD rats, (juvenile and adult) being however twice the increase in Na+ intake. The ATP-dependent Na+ transporters were affected in opposite ways. The (Na+ + K+)ATPase activity from undernourished rats fell by 30%, in parallel with a 20% decrease in its immunodetection, whereas the ouabain-insensitive Na+-ATPase, which is responsible for the fine-tune control of Na+ reabsorption, increased threefold. CONCLUSIONS: We conclude that early alterations in proximal tubule Na+ pumps, together with an abnormally augmented urinary Na+ excretion, might be the link between undernutrition and late renal dysfunction.

Biochemical, functional, and histochemical effects of essential fatty acid deficiency in rat kidney.

The present study was designed to examine the effects of EFA deficiency (EFAD) on biochemical, functional, and structural aspects of the kidney in growing and adult rats fed a normal or EFAD diet for 9 wk after weaning. Food and fluid intake (F1), urine volume, and Na+ and K+ excretions were measured weekly from weeks 4 to 8 by placing the rats in individual metabolic cages for 24 h. At week 9, Li+ and a 5% water load, respectively, were administered at 14 and 1.5 h prior to glomerular and proximal tubular function studies, as assessed by 3-h creatinine (C(Cr)) and Li+ (C(Li+)) clearances. Hematocrit and urine volume; serum and urine [Cr], [Li+], [Na+], and [K+]; and renal FA distribution were also measured. Data [corrected to 100 g/body weight (bw) and presented as means +/- SEM] were significant, at P< or = 0.05. Despite a similar ingestion of solids from weeks 4 to 7 (weeks 7 to 10 of life), the rats on the EFAD diet showed a decreased body weight from week 5. From weeks 4 to 8, Fl and urine volume were similar for both groups, but the Fl increased at week 6 in the EFAD group; 24-h Na+ and K+ excretions were similar at all weeks, except for an increase in the EFAD group for both ions at week 7. In the EFAD group, CCr and CLi+ decreased by 27 and 56.3%, respectively (385.7 +/- 33.4 vs. 280 +/- 21.1, and 21.0 +/- 2.1 vs. 9.2 +/- 1.1 microL/min/100 g; n = 9 vs. 10), the latter result suggesting increased proximal reabsorption. The 3-h Na+ and K+ excretions were similar, but the Li+ decreased (0.78 +/- 0.06 x 10(-2) vs. 0.32 +/- 0.03 x 10(-2) microeq/min/100 g) in the EFAD group, giving additional support to the suggestion. Renal structure was normal and similar for both groups, but the EFAD group showed a more prominent proximal tubule brush border, together with heavier periodic acid-Schiff staining in all specimens from weeks 5 to 9. In the EFAD group, FA of the n-9 and n-7 series were higher, but most of the n-6 series were lower as a percentage of total lipids in the medulla and cortex. Medullary levels of 20:4n-6 were maintained, 22:4n-6 declined twice, arachidonic acid was maintained, and 20:5n-3 was lower. The EFAD diet affected glomerular function, proximal tubular structure and function, and FA distribution in the rat kidney.

O Phyllanthus niruri L. induz caliurese dissociada da diurese e da natriurese em ratos acordados

A validação do P. niruri L. como diurético, ratos acordados em gaiolas metabólicas receberam o infuso a 3 por cento (INF3 por cento) e 5, 10, 25 e 50 mg/kg do extrato etanol: água, por 24, 5 e 3 h respectivamente. A densidade aumentou e a excreção (UV) de K+ na urina diminuiu com o INF3 por cento agudo. As doses 5, 10 e 25 mg/kg alcalinizaram a urina, com caliurese na última. A função glomerular e tubular proximal, as UV de Na+ e K+ não mudaram com 25 mg/kg de P. niruri L.