ANGIOTENSIN-II RECEPTOR-MEDIATED PROLIFERATION OF CULTURED HUMAN FETAL MESANGIAL CELLS

Accumulating evidence suggests that angiotensin II (Ang II) may play an important role in renal growth and glomerular development. During nephrogenesis, a complex relationship between the capillary and renal mesangium develops. Since the mesangial cell is a centrally-located pericyte with contractile, endocrine, and immune modulating functions, it may play a unique role in maintaining normal glomerular function. Therefore, we examined whether Ang II affects proliferation of human fetal mesangial cells in vitro and compared these findings to mesangial cells isolated from adult kidney. In these primary isolates, we studied the relationship between Ang II receptors and the mitogenic activity of angiotensin. Scatchard analysis of the binding of I-125[Sar1, Ile8]Ang II to subconfluent cultured human fetal mesangial cells revealed the presence of one class of binding sites with a Kd of 1.25 nM and a B(max) of 70 fmol/1 x 10(5) cells. Ang II receptors on adult mesangial cells had similar binding kinetics with a Kd of 1.6 nM and B(max) of 65 fmol/10(5) cells in subconfluent culture. In subconfluent culture of fetal mesangial cells, Ang II increased [H-3]thymidine incorporation by 130% (P < 0.005). In subconfluent culture of adult mesangial cells, Ang II increased [H-3]thymidine incorporation by only 35% (P < 0.05). In confluent culture of fetal mesangial cells, Ang II receptor number and mitogenic response were reduced. The Ang II antagonist [Sar1,Ile8]Ang II (1-mu-M) inhibited the mitogenic response of fetal mesangial cells to Ang II. Ang II increased fetal mesangial cell number by 25% (after 4 days) in serum-free medium supplemented with insulin or supplemented with insulin and 1% Nutridoma (P < 0.005). Thus, Ang II is mitogenic for fetal mesangial cells but, in contrast, Ang II is only weakly mitogenic for adult mesangial cells. These results are consistent with a role for Ang II in glomerular development as well as in disease states in which there is a change from the adult to the fetal phenotype.