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

• Published in: British journal of nutrition 2014-06, Vol.111 (11), p.1932-1944
• Main Authors: Vieira-Filho, Leucio D., Cabral, Edjair V., Farias, Juliane S., Silva, Paulo A., Muzi-Filho, Humberto, Vieyra, Adalberto, Paixão, Ana D. O.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; alpha-Tocopherol - administration & dosage; Angiotensin II - genetics; Angiotensin II - metabolism; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Developmental Biology; Diet, Protein-Restricted - adverse effects; Down-Regulation; Experimental diseases; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Glutathione - metabolism; Hypertension; Hypertension - etiology; Hypertension - physiopathology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidneys; Lipid Peroxidation - drug effects; Male; Malnutrition; Malnutrition - complications; Malnutrition - physiopathology; Medical sciences; Metabolic diseases; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Offspring; Other nutritional diseases (malnutrition, nutritional and vitamin deficiencies...); Peroxidation; Pregnancy; Prenatal development; Prenatal Exposure Delayed Effects; Protein Kinase C - genetics; Protein Kinase C - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Receptors, Angiotensin - genetics; Receptors, Angiotensin - metabolism; Rodents; Sodium, Dietary - administration & dosage; Sodium, Dietary - adverse effects; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0007-1145; 1475-2662
• DOI: 10.1017/S0007114513004236

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.