In contrast to the negative feedback of angiotensin II (Ang II) on juxtaglomerular (JG) renin, Ang II stimulates renin in the principal cells of the collecting duct (CD) in rats and mice via Ang II type 1 (AT1R) receptor, independently of blood pressure. In vitro data indicate that CD renin is augmented by AT1R activation through PKC, but the exact mechanisms are unknown. We hypothesize that Ang II stimulates CD renin synthesis through AT1R via PKC and the subsequent activation of cAMP/PKA/CREB pathway. In M-1 cells, Ang II increased cAMP, renin mRNA (3.5 fold), prorenin and renin proteins, as well as renin activity in culture media (2 fold). These effects were prevented by PKC inhibition with calphostin C, PKC-alpha dominant negative and by PKA inhibition. Forskolin-induced increases in cAMP and renin expression were prevented by calphostin C. PKC inhibition and Ca2+ depletion impaired Ang II-mediated CREB phosphorylation and upregulation of renin. Adenylate cyclase 6 (AC) siRNA remarkably attenuated the Ang II-dependent upregulation of renin mRNA. Physiological activation of AC with vasopressin increased renin expression in M-1 cells. The results suggest that the Ang II-dependent upregulation of renin in the CD depends on PKCα, which allows the augmentation of cAMP production and activation of PKA/CREB pathway via AC6. This study defines the intracellular signaling pathway involved in the Ang II-mediated stimulation of renin in the CD. This is a novel mechanism responsible for the regulation of local RAS in the distal nephron.