Natriuretic effect of bufalin in isolated rat kidneys involves activation of the Na+-K+-ATPase-Src kinase pathway

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 inter...

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Published in:	American journal of physiology. Renal physiology Vol. 302; no. 8; p. F959
Main Authors:	Arnaud-Batista, Francisco J, Costa, Graciana T, Oliveira, Ilana Mara Barbosa de, Costa, Paula P C, Santos, Cláudia F, Fonteles, Manassés C, Uchôa, Daniel E, Silveira, Edilberto R, Cardi, Bruno A, Carvalho, Krishnamurti M, Amaral, Luciana S, Pôças, Elisa S C, Quintas, Luis E M, Noël, François, Nascimento, Nilberto R F
Format:	Journal Article
Language:	English
Published:	United States 15-04-2012
Subjects:	Animals Bufanolides - pharmacology Butadienes - pharmacology Diuresis - drug effects Enzyme Inhibitors - pharmacology Kidney - drug effects Kidney - enzymology Male MAP Kinase Kinase 1 - antagonists & inhibitors MAP Kinase Kinase 2 - antagonists & inhibitors Natriuresis - drug effects Natriuretic Agents - pharmacology Nitriles - pharmacology Ouabain Potassium - urine Pyrimidines - pharmacology Rats Rats, Wistar Signal Transduction - drug effects Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors Sodium-Potassium-Exchanging ATPase - metabolism src-Family Kinases - antagonists & inhibitors src-Family Kinases - metabolism
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Summary:	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 profoundly 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 IC(50) (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.
ISSN:	1522-1466
DOI:	10.1152/ajprenal.00130.2011