The angiotensin receptor type 1-Gq protein-phosphatidyl inositol phospholipase Cbeta-protein kinase C pathway is involved in activation of proximal tubule Na+-ATPase activity by angiotensin(1-7) in pig kidneys.
In a previous study, we observed that angiotensin(1-7) (Ang(1-7)) stimulates proximal tubule Na+-ATPase activity through the angiotensin receptor type 1 (AT1R). Here we aimed to study the signalling pathways involved. Our results show that the stimulatory effect of Ang(1-7) on Na+-ATPase activity through AT1R involves a Gq protein-phosphatidyl inositol-phospholipase Cbeta (PI-PLCbeta) pathway because: (1) the effect was reversed by GDPbetaS, a non-hydrolysable GDP analogue, and by a monoclonal Gq protein antibody; (2) the effect was similar and not additive to that of GTPgammaS, a non-hydrolysable GTP analogue; (3) Ang(1-7) induced a rapid decrease (30 s) in phosphatidylinositol 4,5-bisphosphate levels, a PI-PLCbeta substrate; and (4) U73122, a specific inhibitor of PI-PLCbeta, abolished Ang(1-7)-induced stimulation of Na+-ATPase activity. Angiotensin(1-7) increased the protein kinase C (PKC) activity similarly to phorbol-12-myristate-13-acetate (PMA), an activator of PKC. This effect was reversed by losartan, a specific antagonist of AT1R. The stimulatory effects of Ang(1-7) and PMA on Na+-ATPase activity are similar, non-additive and reversed by calphostin C, a specific inhibitor of PKC. A catalytic subunit of PKC (PKC-M) increased the Na+-ATPase activity. These data show that Ang(1-7) stimulates Na+-ATPase activity through the AT1R-Gq protein-PI-PLCbeta-PKC pathway. This effect is similar to that described for angiotensin II, showing for the first time that these compounds could have similar effects in the renal system.
Lara
Lucienne S
LS
Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Brazil.
Correa
Juliana S
JS
Lavelle
Anouchka B
AB
Lopes
Anibal G
AG
Caruso-Neves
Celso
C
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D027682:Cation Transport Proteins / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D006898:Hydroxylamines / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000502:physiology*; D054799:Phospholipase C beta / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012964:Sodium / Q000652:urine; D013552:Swine
D027682:Cation Transport Proteins; D004075:Diglycerides; D006898:Hydroxylamines; D010446:Peptide Fragments; D010716:Phosphatidylinositols; D044140:Receptor, Angiotensin, Type 1; D000803:Angiotensin I; D012964:Sodium; D011493:Protein Kinase C; D054799:Phospholipase C beta; D000251:Adenosine Triphosphatases; C021838:sodium-translocating ATPase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C118790:angiotensin I (1-7)