PKA-mediated effect of MAS receptor in counteracting angiotensin II-stimulated renal Na+-ATPase

Abstract

We showed previously that angiotensin-(1-7) [Ang-(1-7)] reversed stimulation of proximal tubule Na+-ATPase promoted by angiotensin II (Ang II) through a D-ala(7)-Ang-(1-7) (A779)-sensitive receptor. Here we investigated the signaling pathway coupled to this receptor. According to our data, Ang-(1-7) produces a MAS-mediated reversal of Ang II-stimulated Na+-ATPase by a Gs/PKA pathway because: (1) the Ang-(1-7) effect is reversed by GDPbetaS, an inhibitor of trimeric G protein and Gs polyclonal antibody. Cholera toxin, an activator of Gs protein, mimicked it; (2) in the presence of Ang II, Ang-(1-7) increased the PKA activity 10-fold; (3) the peptide inhibitor of PKA blocked the Ang-(1-7) effect on Ang II-stimulated Na+-ATPase; (4) Ang-(1-7) reverses the Ang II-stimulated PKC activity; (5) cAMP mimicked the Ang-(1-7) effect on the Ang II-stimulated Na+-ATPase. Our results provide new understanding about the signaling mechanisms coupled to MAS receptor-mediated renal Ang-(1-7) effects.

Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1–7/Mas axis

“…mary cultures of rat proximal tubular cells, ANG1-7 blocked ANGII-stimulated phosphorylation of p38, ERK1/2, and JNK and partially inhibited ANGII-induced activation of TGF-␤ 1 (20). In perfused kidney preparations, ANG1-7 reversed the stimulation of proximal tubule Na ϩ -ATPase promoted by ANG II (8). In the proximal tubule, ANG1-7 blocks the activation of MAP kinases by ANGII and also activates a tyrosine phosphatase (5).…”

“…ACE-2 is one of the enzymes that degrades ANGII by removal of the COOH-terminal phenylalanine to yield ANG1-7 (12). In nonpulmonary systems, ANG1-7 has been shown to inhibit some of the actions of ANGII; the inhibition is not through competition for occupancy of ANG receptors AT1 or AT2, but rather through the ANG1-7 receptor mas, the protein product of the mas oncogene (5,8,21). In the lungs, the type II pneumocyte is believed to be the only cell that expresses ACE-2, at least in the adult mouse lung (30).…”

Altered signaling pathways linked to angiotensin II underpin the upregulation of renal Na+-ATPase in chronically undernourished rats

“…7) would also contribute to activation of the pump because this kinase has been implicated in 2 different inhibitory pathways of Na + -ATPase, i.e. those linked to AT 2 R [39,42] and ceramide receptors [49]. As discussed above, these alterations may be a consequence of increased local activity of Ang II in the tubulointerstitium, which can stimulate translocation of the upregulated PKCs to the membranes after binding to AT 1 R [50].…”

“…These modifications might be related to an impact of chronic undernutrition in the balance between PKC and PKA. PKC is a key activator of Na + -ATPase in a signaling regulatory pathway that begins at the level of AT 1 R [11], whereas PKA -linked to AT 2 R -is probably a depressor of the pump [39]. Thus, we propose that the increased affinity in Na + binding required for ATP binding and catalytic phosphoryl transfer [42] is due to an increased local activity of the Ang II-stimulated signaling pathway.…”

“…6 shows a selective undernutrition-induced -though quantitatively different -increase in the abundance of isoforms α (55%, Panel A), λ (125%, Panel C), ζ (55%, Panel D) (P b 0.001), and ε (35%, Panel B) (P b 0.01). The next step was the investigation of the abundance of PKA, which is a counterbalancing kinase of Na + -ATPase [39]. Abundance of the α-catalytic subunit of PKA decreased by N55% (P b 0.001) in the proximal tubule cells of BRD rats (Fig.…”