Figure 1

Angiotensin II, transforming growth factor-β, and Smad signaling pathways. Binding of angiotensin II (AngII) to the angiotensin type 1 receptor (AT₁) results in Smad2 and Smad3 phosphorylation via the ERK/p38/MAPK pathway. Activated Smad2 and Smad3 complex with Smad4 and translocate into the nucleus resulting in transcription of target genes including transforming growth factor-β (TGF-β), procollagen I, procollagen III, and fibronectin. AngII-AT₁ binding also directly activates TGF-β, which in turn activates Smad signaling in a similar manner. The P-Smad2/3-Smad4 complex induces transcription of Smad7, which has an inhibitory effect on TGF-β by targeting TGF-β receptor I (TGF-βR1) and Smads for ubiquitin-dependent degradation. Smad7 also inhibits NF-κB-driven inflammation via induction of the NF-κB inhibitor, IκBα. Conversely, activation of the AngII type 2 receptor (AT₂) signaling has an inhibitory effect on both Smad and MAPK signaling pathways via dephosphorylating actions of phosphotyrosine phosphatase and protein phosphatase 2A. This produces antiproliferative and survival-promoting effects that oppose AT₁-mediated fibrotic changes. Green lines indicate positive regulation. Red lines indicate negative regulation. Latent TGF-β binding protein (LTBP), TGF-β receptor 2 (TGF-βIIR), thrombospondin-1 (TSP-1), extracellular signal-relate kinase (ERK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inhibitor of kappa B alpha (IκBα), protein serine/threonine phosphatase 2A (PP2A), phosphotyrosine phosphatase (PTP).