Stimulatory effect of insulin on H+-ATPase in the proximal tubule via the Akt/mTORC2 pathway.
Physiol Int
; 107(3): 376-389, 2020 Oct 17.
Article
em En
| MEDLINE
| ID: mdl-32990653
ABSTRACT
PURPOSE:
Acid-base transport in renal proximal tubules (PTs) is mainly sodium-dependent and conducted in coordination by the apical Na+/H+ exchanger (NHE3), vacuolar H+-adenosine triphosphatase (V-ATPase), and the basolateral Na+/HCO3- cotransporter. V-ATPase on PTs is well-known to play an important role in proton excretion. Recently we reported a stimulatory effect of insulin on these transporters. However, it is unclear whether insulin is involved in acid-base balance in PTs. Thus, we assessed the role of insulin in acid-base balance in PTs.METHODS:
V-ATPase activity was evaluated using freshly isolated PTs obtained from mice, and specific inhibitors were then used to assess the signaling pathways involved in the observed effects.RESULTS:
V-ATPase activity in PTs was markedly enhanced by insulin, and its activation was completely inhibited by bafilomycin (a V-ATPase-specific inhibitor), Akt inhibitor VIII, and PP242 (an mTORC1/2 inhibitor), but not by rapamycin (an mTORC1 inhibitor). V-ATPase activity was stimulated by 1 nm insulin by approximately 20% above baseline, which was completely suppressed by Akt1/2 inhibitor VIII. PP242 completely suppressed the insulin-mediated V-ATPase stimulation in mouse PTs, whereas rapamycin failed to influence the effect of insulin. Insulin-induced Akt phosphorylation in the mouse renal cortex was completely suppressed by Akt1/2 inhibitor VIII and PP242, but not by rapamycin.CONCLUSION:
Our results indicate that stimulation of V-ATPase activity by insulin in PTs is mediated via the Akt2/mTORC2 pathway. These results reveal the mechanism underlying the complex signaling in PT acid-base balance, providing treatment targets for renal disease.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
ATPases Translocadoras de Prótons
/
Proteínas Proto-Oncogênicas c-akt
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Alvo Mecanístico do Complexo 2 de Rapamicina
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Insulina
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Túbulos Renais Proximais
Limite:
Animals
Idioma:
En
Revista:
Physiol Int
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Japão