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.