ANGIOTENSIN-II STIMULATES HUMAN FETAL MESANGIAL CELL-PROLIFERATION AND FIBRONECTIN BIOSYNTHESIS BY BINDING TO AT(1) RECEPTORS

The renin-angiotensin system is activated during vascular development and injury. Furthermore, angiotensin II (Ang II) is a comitogen for fe tal mesangial cells in vitro and it may be important in vascular smoot h cell growth in disease states. Since fibronectin is an important ext racellular matrix protein for vascular development and it too is overe xpressed in the mesangium of diseased glomeruli, we explored the inter relationship of fibronectin and Ang II in fetal mesangial cell growth. In human fetal kidney, Ang II type 2 receptors (AT2) were detected in abundance by ex vivo autoradiography. When mesangial cells were isola ted from fetal kidney and grown in culture, Ang II type 1 receptors (A T1) were also detected. To explore the mitogenic properties Ang II and fibronectin as well as the effects of Ang II on fibronectin metabolis m, studies were performed in vitro, isolated from the potentially conf ounding variables of hemodynamic influence and circulating growth fact ors and cytokines. In vitro, mesangial cells expressed a single class of AT1 receptors that were not altered by growth on various substrates . Ang II (10(-7) M) significantly increased thymidine incorporation by confluent human fetal mesangial cells (twofold). When subconfluent, A ng II-stimulated proliferation was greater (fourfold). Ang II signific antly increased cell-associated and secreted fibronectin as determined by immunoprecipitation at concentrations that also stimulate mitogene sis. Both of these Ang II-mediated responses were inhibited by the AT1 receptor antagonist DuP-753 (10(-5) m) but not by AT1 receptor antago nist. These data suggest that when bound to AT2 receptors expressed on human fetal mesangial cells, Ang II directly stimulates fibronectin p roduction and cellular proliferation independently of its effects on r enal and systemic hemodynamics. Furthermore, the AT1 receptor subtype may well participate in the regulation of fibronectin synthesis during development and in disease.