Aldosterone Signaling in Epithelial Cells

Aldosterone is a steroid hormone that is primarily produced in the outer layer of the adrenal cortex. It plays a major role in Na+, K+, and H+ homeostasis by promoting retention of sodium, regulation of potassium, and the secondary retention of water through transcriptional and translational regulation of electrolyte transport.Sodium enters the renal epithelial cells from luminal compartment through epithelial sodium channels (ENaC)in the apical membrane before it is actively transported out of the cell by the basolateral Na+/K+-ATPase pumps. The pleiotropic action of aldosterone in epithelia is mediated by transcription and post-transcription mechanisms, primarily mediated by the intracellular mineralocorticoid receptor (MR), specifically referred to as classical aldosterone receptor. After hormone binding, the aldosterone-MR complex undergoes a conformational change and subsequent translocation to the nucleus. Once in the nucleus, the complex binds to the steroid response element (SRE) on target genes. Short-term aldosterone effects include the activation of intracellular second messengers like PLC, IP3, DAG, PKC and an increase in free intracellular Ca2+.One generalized view of the actions of aldosterone on epithelia is that the aldosterone programs the cell to "differentiate" more towards a Na+-reabsorbing state and that KRas2A and SGK are early messengers of this signal. Aldosterone induces and activates both KRas2A and SGK via a PI3K pathway. In addition, aldosterone promotes the production of PIP2, a substrate of PI3K and a direct modulator of Na+ channels that are already present on the surface membrane. An additional site of possible cross-talk regulation is between MAPKs and SGK, as MAPK signaling in response to stimulation of Raf induces expression of SGK. Thus, the end results of aldosterone signaling are the activation of KRas2A, PI3K, and SGK, all of which stimulate ENaC activity.Aldosterone via PKC regulates the membrane-associated methyl transferases by controlling the cytosolic concentrations of the end product of methylation, S-adenosyl-homocysteine (SAH) by activating the SAH Hydrolases. SAH is the product that is produced when the endogenous methyl donor, S-adenosyl methionine (SAM) transfers its methyl group to KRas2A. Aldosterone induces expression of Na+ channel, K+ Channel, and the Na+/K+ ATPase pump at the level of transcription. In addition to these transport proteins, aldosterone induces expression of the luminal Na+/H+ antiporter in the proximal but not distal portion of the colon and the luminal, thiazide-sensitive Na+-Cl- cotransporter in the distal renal tubule.Aldosterone is important for the control of blood pressure through the promotion of sodium reabsorption in the kidney and colon. It has also been implicated in the pathogenesis of cardiac fibrosis. A deficiency in aldosterone can occur by itself or, more commonly, in conjunction with a glucocorticoid deficiency, and is known as hypoadrenocorticism or Addison's disease.