Angiotensin II stimulates human fetal mesangial cell proliferation and fibronectin biosynthesis by binding to AT1 receptors.
The renin-angiotensin system is activated during vascular development and injury. Furthermore, angiotensin II (Ang II) is a comitogen for fetal mesangial cells in vitro and it may be important in vascular smooth cell growth in disease states. Since fibronectin is an important extracellular matrix protein for vascular development and it too is overexpressed in the mesangium of diseased glomeruli, we explored the interrelationship 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 isolated from fetal kidney and grown in culture, Ang II type 1 receptors (AT1) were also detected. To explore the mitogenic properties Ang II and fibronectin as well as the effects of Ang II on fibronectin metabolism, studies were performed in vitro, isolated from the potentially confounding variables of hemodynamic influence and circulating growth factors 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, Ang II-stimulated proliferation was greater (fourfold). Ang II significantly increased cell-associated and secreted fibronectin as determined by immunoprecipitation at concentrations that also stimulate mitogenesis. Both of these Ang II-mediated responses were inhibited by the AT1 receptor antagonist DuP-753 (10(-5) M) but not by AT2 receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
Ray
P E
PE
Laboratory of Developmental Biology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland.
Bruggeman
L A
LA
Horikoshi
S
S
Aguilera
G
G
Klotman
P E
PE
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D005333:Fetus / Q000166:cytology* / Q000187:drug effects; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000196:embryology*; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism*
D005353:Fibronectins; D007797:Laminin; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D004247:DNA