Aldosterone acts via an ATP autocrine/paracrine system: the Edelman ATP hypothesis revisited.
Aldosterone, the most important sodium-retaining hormone, was first characterized >50 years ago. However, despite numerous studies including the classical work of Isidore S. "Izzy" Edelman showing that aldosterone action depended on ATP production, the mechanism by which it activates sodium reabsorption via the epithelial sodium channel remains unclear. Here, we report experiments that suggest that one of the key steps in aldosterone action is via an autocrine/paracrine system. The hormone stimulates ATP release from the basolateral side of the target kidney cell. Prevention of ATP accumulation or its removal blocks aldosterone action. ATP then acts via a purinergic mechanism to produce contraction of small groups of adjacent epithelial cells. Patch clamping demonstrates that it is these contracted cells that have channel activity. With progressive recruitment of contracting cells, there is then a parallel increase in transepithelial electrical conductance. In common with other stimuli of sodium transport, this pathway involves phosphatidylinositol 3-kinase. Inhibition of phosphatidylinositol 3-kinase blocks both cell contraction and conductance. We put forward the hypothesis that redistribution of the cell volume caused by the lateral contraction results in apical swelling and that this change, in turn, disrupts the epithelial sodium channel interaction with the F-actin cytoskeleton, opening the channel and hence increasing sodium transport.
Gorelik
Julia
J
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Zhang
Yanjun
Y
Sánchez
Daniel
D
Shevchuk
Andrew
A
Frolenkov
Gregory
G
Lab
Max
M
Klenerman
David
D
Edwards
Christopher
C
Korchev
Yuri
Y
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D002460:Cell Line; D048430:Cell Shape; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D053503:Epithelial Sodium Channels; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008853:Microscopy / Q000379:methods; D008962:Models, Theoretical; D019899:Paracrine Communication; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*
D053503:Epithelial Sodium Channels; D015222:Sodium Channels; D000450:Aldosterone; D000255:Adenosine Triphosphate; D012964:Sodium