ATP and the Response to Aldosterone

Abstract

It has been known for many years that adenosine 5′-triphosphate (ATP) production is necessary for the stimulation of sodium reabsorption by aldosterone, a hormone that plays a critical role in regulating sodium homeostasis. However, the exact mechanism whereby aldosterone stimulates sodium reabsorption--and the precise role of ATP in mediating its effects--has been unclear. Using scanning ion conductance microscopy to image the apical membranes of A6 renal epithelial cells in monolayer culture, Gorelik et al. observed that aldosterone produced morphological changes consistent with contraction of clusters of cells. This contraction, which resembled that elicited by hypoosmotic stress of the basolateral surface, was associated with loss of the normal architecture of the microvilli. The progressive recruitment of contracted cells paralleled an increase in Na + permeability of the epithelial sodium channel (ENaC, measured as an amiloride-sensitive increase in transepithelial conductance, G t ENaC ). However, aldosterone-mediated contraction was not sensitive to amiloride but was sensitive to phosphatidylinositol 3-kinase (PI3K) inhibition (which also blocked the increase in conductance). Moreover, patch-clamp analysis of contracted and noncontracted cells revealed that only contracted cells showed ENaC activity. Aldosterone also stimulated basolateral release of ATP, and the nonhydrolyzable ATP analog ATPγS stimulated both G t ENaC and cell contraction. In contrast, trapping free ATP by adding glucose and hexokinase to the basolateral solution eliminated the effects of aldosterone on conductance, as did treatment with a P1 receptor antagonist. Thus, the authors propose that aldosterone stimulates the release of ATP, which, through a purinergic mechanism, stimulates autocrine and paracrine contraction, leading to reorganization of the apical membrane and activation of apical ENaC in the early phase of aldosterone action. J. Gorelik, Y. Zhang, D. Sánchez, A. Shevchuk, G. Frolenkov, M. Lab, D. Klenerman, C. Edwards, Y. Korchev, Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited. Proc. Natl. Acad. Sci. U.S.A. 102 , 15000-15005 (2005). [Abstract] [Full Text]