Natriuretic effect of bufalin in isolated rat kidneys involves activation of the Na+-K+-ATPase-Src kinase pathway
Autor: | Nilberto R.F. Nascimento, Ilana Mara Barbosa de Oliveira, Elisa Suzana Carneiro Pôças, Cláudia F. Santos, Luis Eduardo M. Quintas, Daniel Esdras de Andrade Uchoa, Graciana T. Costa, Bruno A. Cardi, Krishnamurti M. Carvalho, Luciana S. Amaral, François Noël, Manassés C. Fonteles, Edilberto R. Silveira, Paula Priscila Correia Costa, Francisco J. Arnaud-Batista |
---|---|
Rok vydání: | 2012 |
Předmět: |
Male
medicine.medical_specialty Digoxin Physiology medicine.medical_treatment MAP Kinase Kinase 2 MAP Kinase Kinase 1 Natriuresis Endogeny Kidney Ouabain Steroid Internal medicine Nitriles medicine Butadienes Animals Na+/K+-ATPase Enzyme Inhibitors Rats Wistar Chemistry Bufalin Diuresis Rats Bufanolides Endocrinology Pyrimidines src-Family Kinases Potassium Natriuretic Agents Sodium-Potassium-Exchanging ATPase medicine.drug Proto-oncogene tyrosine-protein kinase Src Hormone Signal Transduction |
Zdroj: | American journal of physiology. Renal physiology. 302(8) |
ISSN: | 1522-1466 |
Popis: | Bufadienolides are structurally related to the clinically relevant cardenolides (e.g., digoxin) and are now considered as endogenous steroid hormones. Binding of ouabain to Na+-K+-ATPase has been associated, in kidney cells, to the activation of the Src kinase pathway and Na+-K+-ATPase internalization. Nevertheless, whether the activation of this cascade also occurs with other cardiotonic steroids and leads to diuresis and natriuresis in the isolated intact kidney is still unknown. In the present work, we perfused rat kidneys for 120 min with bufalin (1, 3, or 10 μM) and measured its vascular and tubular effects. Thereafter, we probed the effect of 10 μM 3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4amine (PP2), a Src family kinase inhibitor, and 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (UO126), a highly selective inhibitor of both MEK1 and MEK2, on bufalin-induced renal alterations. Bufalin at 3 and 10 μM profundly increased several parameters of renal function in a time- and/or concentration-dependent fashion. At a concentration that produced similar inhibition of the rat kidney Na+-K+-ATPase, ouabain had a much smaller diuretic and natriuretic effect. Although bufalin fully inhibited the rat kidney Na+-K+-ATPase in vitro, its IC50(33 ± 1 μM) was threefold higher than the concentration used ex vivo and all its renal effects were blunted by PP2 and UO126. Furthermore, the phosphorylated (activated) ERK1/2 expression was increased after bufalin perfusion and this effect was totally prevented after PP2 pretreatment. The present study shows for the first time the direct diuretic, natriuretic, and kaliuretic effects of bufalin in isolated rat kidney and the relevance of Na+-K+-ATPase-mediated signal transduction. |
Databáze: | OpenAIRE |
Externí odkaz: |