Angiotensins (Angiotensin-I and II), the main peptides of the renin-angiotensin system, are prominent growth factor for vascular smooth muscle cells (VSMC). Renin is an enzyme that proteolytically cleaves a circulating substrate called angiotensinogen to produce the decapeptide Angiotensin-I. Vascular endothelium, particularly in the lungs, has an enzyme called angiotensin converting enzyme (ACE) that cleaves off two amino acids to form the octapeptide, Angiotensin-II. Multiple signal transduction pathways are involved in mediating angiotensin receptor stimulation of cell proliferation, cell migration, and other responses.Angiotensin-II is a potent renal growth factor, inducing hyperplasia/hypertrophy depending on the cell type. These effects are mediated by the release of several factors, including TGF-β and PAI1. Angiotensin-II receptors AgtR1 and AgtR2 act through Gαq and Gαi proteins, respectively. Angiotensin-II, via AgtR1, activates the transcription factor STAT. Angiotensin-II increases Ca2+ release and activates PKC, Pyk2, Src and FAK, IKK and their downstream effectors such as Elk1, AP-1, as well as the ERK, p38 MAPK, and JNK pathways. The signaling through Gαq activates Rac1 which in turn activates PAK1. PAK1 induces the JNK cascade, including MEKK1/2, SEK1, and JNK, and causes induction of AP-1 mediated transcrition. Angiotensin-II binding to AgtR1 also stimulates PLC to hydrolyze PIP2 to generating IP3 and DAG. The intracellular mechanisms elicited by AgtR2 are ceramide production and activation of PPTase. Ceramide production is involved in apoptosis and NF-κB activation. Other important candidates of the AgtR2-NF-κB pathway are iNOS and COX2 , which in inflammatory diseases are involved in NO, cGMP, prostaglandin and thromboxane production. Angiotensin-II may cause growth via AgtR1 and apoptosis via AgtR2. Activation of the renin-angiotensin System also enhances the vascular production of ROS, in part through the activation of membrane-bound NADH and NADPH Oxidases. Angiotensin-II binding stimulates tyrosine phosphorylation of the linker protein SHC, which then interacts with the GRB2-SOS complex, causing activation of Ras. Ras/Raf then stimulates ERK1/2, which phosphorylates the transcription factor Elk1 leading to the production of MCPs, TGF-β, c-Fos and PAI. In VSMC, Angiotensin-II increases production of prostaglandins, as well as activating adenylate cyclase, increasing cAMP, and stimulating PKA.
Angiotensin-II is involved in the inflammatory process during renal injury. It activates inflammatory cells by direct chemotaxis and production of proinflammatory mediators such as VCAM, MCP1, IL-6, and TGF-β. It contributes to the ongoing inflammation, facilitating the migration of mononuclear cells to the interstitium and glomeruli where they undergo maturation/differentiation into macrophages and ultimately participate in fibrogenesis. These inflammatory cells in turn activate renal cells through the release of growth factors, including Angiotensin-II, and therefore contribute to the perpetuation of kidney damage. Angiotensin-II regulates mesangial cell growth, inducing proliferation or hypertrophy depending on the intracellular balance between growth factors, and increases the expression and synthesis of ECM proteins, such as fibronectin, laminin, and collagens.