Regulation of cell proliferation and growth by angiotensin II

The peptide hormone angiotensin II (AngII) has clearly defined physiologic roles as a regulator of vasomotor tone and fluid homeostasis. In addition AngII has trophic or mitogenic effects on a variety of target tissues, including vascular smooth muscle and adrenal cells. More recent data indicate that AngII exhibits many characteristics of the ‘classical’ peptide growth factors such as $\text{EGF}\text{TGFα}$, PDGF and IGF-1. These include the capacity for local generation (‘autocrine or paracrine’ action) and the ability to stimulate tyrosine phosphorylation, to activate MAP kinases and to increase expression of nuclear proto-oncogenes. The type 1 AngII receptor, which is responsible for all known physiologic actions of AngII, has been cloned. Activation of this receptor leads to elevated phosphoinositide hydrolysis, mobilization of intracellular Ca²⁺ and diacylglycerol, and activation of $\text{Ca}{}^{\mathrm{2+}}\text{calmodulin}$ and $\text{Ca}{}^{\mathrm{2+}}\text{phospholipid}\text{-}\text{dependent}$$\text{Ser}\text{Thr}$ kinases, as well as Ca²⁺ regulated tyrosine kinases. The existence of other AngII receptor subtypes has been postulated, but the function(s) of these sites remains unclear. In vascular smooth muscle, AngII can promote cellular hypertrophy and/or hyperplasia, depending in part on the patterns of induction of secondary factors that are known to stimulate (PDGF, IGF-1, basic FGF) or inhibit (TGF-β) mitosis. Together, these findings have suggested that AngII plays important roles in both the normal development and pathophysiology of vascular, cardiac, renal and central nervous system tissues.