The importance of the kidney in the development of hypertension was first demonstrated by Goldblatt and his colleagues more than fifty years ago. Many hormones and other regulatory factors have been proposed to play a major role in the development of hypertension. Among these factors angiotensin II (ANG II) is closely involved in renal hypertension development since it directly regulates Na+ reabsorption in the renal proximal tubule. Thus the aim of the present study was to examine signaling pathways of low dose of ANG II on the Na+ uptake of primary cultured rabbit renal proximal tubule cells (PTCs) in hormonally defined serum-free medium. The results were as follows: 1) 10-11 M ANG II has a significant stimulatory effect on growth as compared with control. Alkaline phosphatase exhibited significantly increased activity. However, leucine aminopeptidase and γ-glutamyl transpeptidase activity were not significant as compared with control. In contrast to 10-11 M ANG II stimulated Na+ uptake (108.03⁑2.16% of that of control), 10-9 M ANG II inhibited (92.42⁑2.23% of that of control). The stimulatory effect of ANG II on Na+ uptake was amiloride-sensitive and inhibited by losartan (ANG II receptor subtype 1 antagonist) and not by PD123319 (ANG II receptor subtype 2 antagonist). 2) Pertussis toxin (PTX) alone inhibited Na+ uptake by 85.52⁑3.52% of that of control. In addition, PTX pretreatment prevented the ANG II-induced stimulation of Na+ uptake. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), forskolin, and isobutylmethylxanthine (IBMX) alone inhibited Na+ uptake by 88.79⁑2.56, 80.63⁑4.38, and 84.47⁑4.74% of that of control, respectively, and prevented the ANG II-induced stimulation of Na+ uptake. However, 10-11 M ANG II did not stimulate cAMP production. 3) The addition of 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.01 ng/ml) to the PTCs produced significant increase in Na+ uptake (114.43⁑4.05% of that of control). When ANG II and TPA were added together to the PTCs, there was no additive effect on Na+ uptake. Staurosporine alone had no effect on Na+ uptake, but led to a complete inhibition of ANG II- or TPA-induced stimulation of Na+ uptake. ANG II treatment resulted in a 111.83⁑4.51% increase in total protein kinase C (PKC) activity. In conclusion, the PTX-sensitive PKC pathway is the main signaling cascade involved in the stimulatory effects of ANG II on Na+ uptake in the PTCs.