Crosstalk between the signaling pathways triggered by angiotensin II and adenosine in the renal proximal tubules: Implications for modulation of Na+-ATPase activity

We have previously demonstrated that adenosine (Ado) reverses the stimulatory effect of angiotensin II (Ang II) on Na+-ATPase activity via the A(2A) receptor, In this work, the molecular mechanism involved in Ado-induced shutdown in the signaling pathway triggered by 10 8 M Ang 11 was investigated. It was observed that: (1) both 10(-12) M PMA (a PKC activator) and 5 x 10 (8) M U73122 (an inhibitor of PI-PLC beta) prevent the reversion effect induced by 10 6 M Ado (only observed in the presence of 10 (6) M DPCPX (an A, receptor antagonist)) on Ang II-stimulated Na+-ATPase and PKC activities; (2) Ang II-stimulated PKC activity was reversed by 10 (6) M forskolin (an adenylyl cyclase activator) or 10 (8) M PKA inhibitory peptide and 10(-8) M DMPX (an A(2) receptor-selective antagonist). Considering that PMA prevents the inhibitory effect of Ado on Ang II-stimulated Na+-ATPase and PKC activities, it is likely that the PMA-induced effect, i.e. PKC activation, is downstream of the target for Ado-induced reversion of Ang II stimulation of Na+-ATPase activity. We investigated the hypothesis that PI-PLC beta could be the target for Ado-induced PKA activation. Our data demonstrate that Ang II-stimulated PI-PLC beta activity was reversed by Ado or 10 (7) M cAMP; the reversibility of the Ado-induced effect was prevented by either DMPX or PKA inhibitory peptide. These data demonstrate that Ado-induced PKA activation reduces Ang II-induced stimulation of PI-PLC beta. (C) 2008 Elsevier Inc. All rights reserved.