Objective To clarify the signaling mechanisms underlying angiotensin Ⅱ biphasic regulation of renal proximal Na+-HCO3- transport. Methods Different concentration Ang Ⅱ to the responses of Na+-HCO3- cotransporter (NBC) activity in isolated proximal tubules, with or without ATR, MAPK, cPLA2α, P450 blockade was compared in wild-type and Ang Ⅱ type 1a receptor (AT1aR)-deficient mice. The phospholipase of ERK was examined by Western blotting. AT1aR mRNA was examined by RT-PCR from kidney proximal tubules. Results (1)In isolated wild-type mouse, renal proximal tubules showed biphasic effects of Ang Ⅱ on NBC activity. Low concentration Ang Ⅱ (10-10 mol/L) increased NBC activity, but high concentration Ang Ⅱ (10-6 mol/L) decreased NBC activity. Olmcsartan (AT1 antagonist) blocked both stimnlatory and inhibitory effects of Ang Ⅱ on NBC activity, but PD98059 (mitogen-activated protein kinase inhibitor) blocked only the stimulatory effect of low concentration Ang Ⅱ ( 10-10 mol/L). (2)In AT1aR-deficient mice, only the stimulatory effect by high concentration of Ang Ⅱ (10-6 mol/L) was observed, which was blocked by olmesartan and PD98059. (3)In wild-type mice, pharmacological blockade of cPLA2 or P450 converted the inhibition effect by high concentration Ang Ⅱ (10-6 mol/L) to the stimulation, which was blocked by olmesanan and PD98059. These results indicated that the extracellular sigual-regulated kinase (ERK) activation via AT1 mediated only the stimulatory effect of Ang Ⅱ, while the cPLA2α/P450 activation via AT1 mediated the inhibitory effect of Ang Ⅱ independently of ERK. The analysis of ERK phosphorylation by Ang Ⅱ also supported a view that the cPLA2α/P450 pathway worked to suppress the ERK activation. Conclusions Ang Ⅱ activates ERK and cPLA2α with different concentration dependency via AT1. The balance between ERK and cPLA2α activities determines the final responses to Ang Ⅱ in intact proximal tubules.