The most significant direct role of estrogen in vivo is its ability to elicit receptor-mediated cellular proliferation in mammalian target tissues. However, the mechanism by which exogenously added estrogen causes the neoplastic transformation of renal cortical cells is yet to be uncovered. The present study was designed to evaluate interaction of 17-estradiol (E2) with epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) on proliferation and Pi uptake in primary cultured rabbit renal proximal tubular cells in phenol red-free, hormonally defined-medium. [3H]-thymidine incorporation increased markedly by about 133% and 141% more in the presence of 109 and 106 M E2, respectively, than that of control. Cell count was 162% and 143% greater in the presence of 109 and 106 M E2 , respectively, compared with control. Among all time points examined, there was an increase in [3H]-thymidine incorporation in the presence of 109 M E2 at day 9 or 13, respectively. However, E2 (109 M) significantly drove up cell count to 160% of that of control at day 13, while it had a slight but statistically insignificant effect at day 9. E2-induced stimulation of [3H]-thymidine incorporation was completely reversed by E2 antagonists (progesterone or tamoxifen). E2 (109 M) or EGF (108 M) significantly stimulated [3H]-thymidine incorporation by 144% and 154% of control. E2 plus EGF was synergistic on [3H]-thymidine incorporation (204% of control), while E2 plus IGF-I showed a slight but no significant synergistic effect. Cell number also displayed similar pattern. E2 (109 M) significantly stimulated Pi uptake to 134% of control. E2-induced stimulation of Pi uptake was partially reversed by E2 antagonists. EGF or IGF-I (108 M) significantly also increased Pi uptake to 132% or 129% of control. E2 plus EGF had synergistic effect on Pi uptake, while E2 plus IGF-I did not. In conclusion, E2 may act not only directly interaction with its receptors but also indirectly as a modulator of EGF in proliferation and Pi uptake of primary cultured rabbit renal proximal tubular cells.
