Both angiotensin II (Ang II) and transforming growth factor-₁ (TGF-₁) are thought to be involved in mediating pulmonary fibrosis. Interactions between the renin-angiotensin system (RAS) and TGF-₁ have been well documented with most studies describing the effect of Ang II on TGF-₁ expression. However, recent gene expression profiling experiments demonstrated that the angiotensin II type 1 receptor (AT₁R) gene was a novel TGF-₁ target in human adult lung fibroblasts. In this report, we show that TGF-₁ augments human AT₁R (hAT₁R) steady state mRNA and protein levels in a dose- and time-dependent manner in primary human fetal pulmonary fibroblasts (hPFBs). Nuclear run-on experiments demonstrate that TGF-₁ transcriptionally activates the hAT₁R gene and does not influence hAT₁R mRNA stability. Pharmacological inhibitors and specific siRNA knockdown experiments demonstrate that the TGF-₁ type 1 receptor (TRI/ALK5), Smad2/3, and Smad4 are essential for TGF-₁-stimulated hAT₁R expression. Additionally, pharmacological inhibitor and siRNA experiments also demonstrated that p38MAPK, JNK and PI3K signaling pathways are also involved in the TGF-₁-stimulated increase in hAT₁R density. Taken together, our results suggest an important role for cross-talk between Smad, p38MAPK, JNK and PI3K pathways in mediating the augmented expression of hAT₁R following TGF-₁ treatment in hPFBs. This study supports the hypothesis that a self-potentiating loop exists between the RAS and the TGF-₁ signaling pathways and suggests that Ang II and TGF-₁ may cooperate in the pathogenesis of pulmonary fibrosis. The synergy between these systems may require that both pathways be simultaneously inhibited in order to treat fibrotic lung disease.