Pleiotropic action of aldosterone in epithelia mediated by transcription and post-transcription mechanisms

The aldosterone-induced increase in sodium reabsorption across tight epithe lia can be divided schematically into two functional phases: an early regul atory phase starting after a lag period of 20 to 60 minutes, during which t he pre-existing transport machinery is activated, and a late phase (>2.5 h) , which can be viewed as an anabolic action leading to a further amplificat ion/differentiation of the Na+ transport machinery. At the transcriptional level, both early and late responses are initiated during the lag period, b ut the functional impact of newly synthesized regulatory proteins is faster than that of the structural ones. K-Ras2 and SGK were identified as the fi rst early aldosterone-induced regulatory proteins in A6 epithelia. Their mR NAs also were shown to be regulated in vivo by aldosterone, and their expre ssion (constitutively active K-Ras2 and wild-type SGK) was shown to increas e the function of ENaC coexpressed in Xenopus oocytes. Recently, aldosteron e was also shown to act on transcription factors in A6 epithelia: It down-r egulates the mRNAs of the proliferation-promoting c-Myc, c-Jun, and c-Fos b y a post-transcriptional mechanism, whereas it up-regulates that. of Fra-2 (c-Fos antagonist) at the transcriptional level. Together, these new data i llustrate the complexity of the regulatory network controlled by aldosteron e and support the view that its early action is mediated by the induction o f key regulatory proteins such as K-Ras2 and SGK. These early induced prote ins are sites of convergence for different regulatory inputs, and thus, the ir aldosterone-regulated expression level tunes the impact of other regulat ory cascades on sodium transport. This suggests mechanisms for the escape f rom aldosterone action.