Aldosterone Signaling in Epithelial Cells
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Aldosterone Signaling in Epithelial Cells
Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal nephron and colon is the major factor determining total body Na+ levels, and thus, long term blood pressure. Aldosterone, a steroid hormone that is primarily produced in the zona glomerulosa, the outer layer of the adrenal cortex, maintains total organism sodium balance in all higher vertebrates (Ref.1). Principally, in humans, aldosterone is involved in the regulation of electrolyte and water balance through its effects on ion transport in epithelial cells. Electrically tight epithelial monolayers, such as the renal distal tubule and collecting duct system, distal colon, and those in salivary glands, are considered classic aldosterone target tissues (Ref.2). Aldosterone 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 (Ref.3).

Sodium enters the renal epithelial cells from luminal compartment through ENaCs (Epithelial Sodium Chalnnels) in the apical membrane before it is actively transported out of the cell by the basolateral Na+/K+-ATPase (Na+, K+-Adenosine Triphophatase) pumps. In epithelial cells, the mineralocorticoid hormone aldosterone stimulates transcellular Na+ reabsorption across target epithelia by first activating preexisting channels and pumps and, subsequently increasing the overall transport capacity of the cells. These effects on the renal collecting duct mediate a major regulatory site for control of body sodium and water, as well as blood pressure regulation (Ref.3). The aldosterone-induced increase in sodium reabsorption across tight epithelia can be divided schematically into two functional phases: an early regulatory phase starting after a lag period of 20 to 60 minutes, during which the 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 amplification/differentiation of the Na+ transport machinery (Ref.4).

Pleiotropic action of aldosterone in epithelia are mediated by transcription and post-transcription mechanisms, primarily mediated by the intracellular MR (Mineralocorticoid Receptor), (specifically referred to as Classical Aldosterone Receptor) which is a nuclear receptor belonging to the superfamily of ligand-regulated transcription factors. MR protein belongs to the steroid hormone receptor family of ligand-dependent transcription factors. Structurally, the receptor consists of three major domains. The first of these is the N-terminal domain, which contains an AF (Activation Function) involved in transcriptional activation. In the middle of the protein is the DNA-binding domain, which binds to specific DNA sequences on target genes. C-terminal to the DNA-binding domain is the LBD (Ligand-Binding Domain), which has sequences involved in ligand binding, transcriptional activation, and HSP (Heat-Shock Protein) binding (Ref.5). After hormone binding, the Aldosterone-MR complex undergoes a conformational change. During this process molecular chaperones such as HSPs bound to the MR are liberated, and the complex is translocated to the nucleus where it acts as a DNA-binding protein that targets SRE (Steroid Response Element) on genetic DNA. Transcription occurs and finally mRNA is exported to be translated into AIPs (Aldosterone-Induced Proteins) at the ribosomes. Aldosterone influences expression of a broad pool of genes, and its actions are pleiotropic, involving regulation of several distinct end-effectors through the amalgamation of diverse intermediaries and signaling inputs (Ref.2).

Aldosterone also affects cellular activity through faster, nongenomic actions mediated presumably by distinct plasma membrane/cytosolic receptors, refered to as, Membrane Aldosterone Receptors (Ref.2). Aldosterone has nongenomic effects mediated by additional signal transduction pathways. Short-term aldosterone effects include the activation of intracellular second messengers: IPYKs (Intermediate Tyrosine Kinases); PLC (Phospholipase-C), IP3 (Inositol Trisphosphate), DAG (Diacylglycerol), PKC (Protein Kinase-C) and an increase in free intracellular Ca2+ (Calcium) (Ref.6). Effects of aldosterone on Na+/H+ Antiporter (the sodium-proton exchanger) is brought about both by IPYK and PKC (Ref.7).

One generalized view of the actions of aldosterone on epithelia is that this steroid programs the cell to "differentiate" more towards a Na+-reabsorbing state and that KRas2A (Kirsten Ras GTP binding protein) and SGK (Serum and Glucocorticoid-Inducible Kinase) are merely the early messengers of this signal (Ref.2). With this signaling cascade, aldosterone would both induce KRas2A and activate this protein through positive-feedback regulation via PI3K (Phosphatidylinositol 3-Kinase)-PDK-1 (Phosphoinositide Dependent Kinase-1)-SOS. Aldosterone would similarly induce SGK expression and promote SGK activation via KRas2A-PI3K-PDK-1. PI3K metabolizes PIP2 (Phosphatidylinositol 4,5-Bisphosphate), to PIP3 (Phosphatidylinositol 3,4,5-Trisphosphate). Aldosterone promotes the production of PIP2, which is a direct modulator of Na+ channels that are already present on the surface membrane, through the action of PIP5K (Phosphatidylinositol-4-Phosphate-5-Kinase). Moreover, this generalized cascade contains multiple converging and diverging pathways, exerting pleiotropic effects on epithelia. An additional site of possible cross-talk regulation is between MAPKs (Mitogen-Activated Protein Kinases) and SGK, as MAPK signaling in response to stimulation of Raf induces expression of SGK (Ref.8). Numerous feedback pathways within the MAPK cascade lessen the initial effect of this cascade on the sodium channels during aldosterone signaling. Aldosterone-induced KRas2A via MAPK signaling leads to induction of MKP1 (MAPK Phosphatase-1), which is a negative-feedback regulator of MAPKs (Ref.3).

The kinase activity of SGK directly or by targeting various proteins, regulates the functioning of the Na+ channels. For example, it phosphorylates a ubiquitin-protein ligase, NEDD4
(Neural Precursor Cell Expressed, Developmentally Downregulated-4) that reduces its affinity for the subunits of the apical epithelial Na+ Channel resulting in post-translational activation of existing sodium channels and increased epithelial sodium transport (Ref.3). PI3K is required for SGK-dependent stimulation of ENaC-mediated Na+ transport as well as for the production of the phosphorylated form of SGK. Thus, the end results of aldosterone signaling are the activation of KRas2A, PI3K, and SGK, all of which stimulate ENaC activity (Ref.8).

Even though KRas2A is an AIP, but to be active, it must be methylated. Aldosterone, through the AIPs like PKC regulate the membrane-associated methyl transferases by controlling the cytosolic concentrations of the end product of methylation, SAH (S-Adenosyl-Homocysteine) by activating the SAH Hydrolases. SAH is the product that is produced when the endogenous methyl donor, SAM (S-Adenosyl Methionine) transfers its methyl group to KRas2A (Ref.3). 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 (Ref.2).

The three principal factors that regulate aldosterone secretion in our body are: Angiotensin-II, ACTH (Adrenocorticotrophic Hormone), and potassium (Ref.5). 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 Addisons disease (Ref.1). Without treatment by mineralocorticoid replacement therapy, aldosterone deficiency is lethal, due to electrolyte imbalances and resulting hypotension and cardiac failure. The three known monogenetic causes of hypertension, glucocorticoid remediable hyperaldosteronism, apparent mineralocorticoid excess, and Liddles syndrome (pseudoaldosteronism), all involve aldosterone, its receptor, or sodium reabsorption (Ref.5).