Aldosterone-induced proteins

Mineralocorticoids foUow a mechanistic route similar to that of glucocorticoids, though differing in the proteins expressed. The activated MR-DNA complex promotes the expression of aldosterone-induced proteins (AIPs), which then act to increase conductance of the luminal membrane and concurrently increase pump activity of the basolateral membrane. These actions result from a number of AlP-influenced cellular characteristics,... 

The mechanism by which Na" is reabsorbed in coupled exchange with and K+ in the collecting duct has been discussed previously that is, Na+-driven K+ secretion is partially under mineralocorticoid control. Aldosterone and other compounds with mineralocorticoid activity bind to a specific mineralocorticoid receptor in the cytoplasm of late distal tubule cells and of principal cells of the collecting ducts. This hormone-receptor complex is transported to the cell nucleus, where it induces synthesis of multiple proteins that are collectively called aldosterone-induced proteins. The precise mechanisms by which these proteins enhance Na+ transport are incompletely understood. However, the net effect is to increase Na" entry across apical cell membranes and to increase basolateral membrane Na+-K+-ATPase activity and synthesis. 

Aldosterone acts on the late distal tubules and collecting tubule cells by combining with an intracellular receptor which induces the formation of aldosterone induced protein, which promotes Na+ reabsorption and K+ secretion. 

Figure 12.6 Mechanism of action of mineralocortjcoid receptor antagonists in the collecting tubule. Aldosterone enters the tubular cell by the basolateral surface and binds to a specific mineralocorticoid receptor (MNR) in the cytoplasm. The hormone receptor complex triggers the production of an aldosterone-induced protein (AlP) by the cell nucleus (NUC). The AIP acts on the sodium ion channel (ic) to augment the transport of Na+across the basolateral membrane and in to the cell. An increase in AIP activity leads to the recruitment of dormant sodium ion channels and Na pumps (P) in the cell membrane. AIP also leads to the synthesis of new channels and pumps within the cell. The increase in Na+conductance causes electrical changes in the luminal membrane that favour the excretion of intracellular cations, such as K+and H-h. Spironolactone competes with aldosterone for the binding site on the MNR and forms a complex which does not excite the production of AIP by the nucleus.

Aldosterone exerts its effect by binding to type I corticosteroid receptors in the cytoplasm, translocating to the nucleus, and binding to an acceptor site in the chromatin, which results in gene activation and synthesis of a specific protein (see Chapter 30). Aldosterone induces the synthesis of aldosterone-induced protein (AIP), which is involved in transcellular Na+,K+-ATPase. 

FIGURE 28-6 Effects of aldosterone on late distal tubule and collecting duct and diuretic mechanism of aldosterone antagonists. AIP, aldosterone-induced proteins ALDO, aldosterone MR, mineralocorticoid receptor CH, ion channel 1, activation of membrane-bound Na channels 2, redistribution of Na" channels from cytosol to membrane 3, de novo synthesis of Na+channels 4, activation of membrane-bound Na , K -ATPase 5, redistribution of Na , K -ATPase from cytosol to membrane 6, de novo synthesis of Na, K -ATPase 7, changes in permeability of tight junctions 8, increased mitochondrial production of ATP. BL and LM indicate basolateral and luminal membranes, respectively. 

Edelman and Fimognari [20] have reviewed published studies on aldosterone s mode of action and have proposed a working hypothesis in which nuclear RNA synthesis and protein synthesis are involved. It is postulated that in the nucleus aldosterone induces the synthesis of new messenger RNA, which in the cytoplasm stimulates the biosynthesis of an enzyme. 

Other investigators have also shown that actinomy-cin interferes with the action of aldosterone in vivo, and that aldosterone binds to a nuclear receptor believed to be a protein. Binding between receptor and aldosterone requires the presence of SH groups on the protein. The role played by the complex of aldosterone and protein in gene expression is still not clear, but the complex of hormone and protein is believed to induce the biosynthesis of a new protein. The most popular hypothesis proposes that the new protein is in some way involved in NADH electron transport and coupled to phosphorylation of ADP. 

Although it is not possible to discuss here the pros and cons of other theories on aldosterone s action, the possibility that the induced protein is either a sodium permease or a protein that stimulates the sodium pump directly has not been excluded. 

The kidney contains the major site of renin synthesis, the juxtaglomerular cells in the wall of the afferent arteriole. From these cells, renin is secreted not only into the circulation but also into the renal interstitium. Moreover, the enzyme is produced albeit in low amounts by proximal tubular cells. These cells also synthesize angiotensinogen and ACE. The RAS proteins interact in the renal interstitium and in the proximal tubular lumen to synthesize angiotensin II. In the proximal tubule, angiotensin II activates the sodium/hydrogen exchanger (NHE) that increases sodium reabsorption. Aldosterone elicits the same effect in the distal tubule by activating epithelial sodium channels (ENaC) and the sodium-potassium-ATPase. Thereby, it also induces water reabsotption and potassium secretion. 

Spironolactone (Aldactone) is structurally related to aldosterone and acts as a competitive inhibitor to prevent the binding of aldosterone to its specific cellular binding protein. Spironolactone thus blocks the hormone-induced stimulation of protein synthesis necessary for Na+ reabsorption and K+ secretion. Spironolactone, in the presence of circulating aldosterone, promotes a modest increase in Na excretion associated with a decrease in elimination. 

Alcoholics with chronic liver disease may have disorders of fluid and electrolyte balance, including ascites, edema, and effusions. These factors may be related to decreased protein synthesis and portal hypertension. Alterations of whole body potassium induced by vomiting and diarrhea, as well as severe secondary aldosteronism, may contribute to muscle weakness and can be worsened by diuretic therapy. Some alcoholic patients develop hypoglycemia, probably as a result of impaired hepatic gluconeogenesis. Some alcoholics also develop ketosis, caused by excessive lipolytic factors, especially increased cortisol and growth hormone. 

Fig. 3. Temporal summation of response. Although the initial (calmodulin-dependent, CaM) and the sustained (C-kinase) phases of All-induced aldosterone secretion are mediated by different protein kinases, their activities are integrated to produce a monotonic rather than a biphasic secretory response.

Alanine-TR, [3-alanine transporter ALDH, aldehyde dehydrogenase ALDO-R, aldosterone receptor Aik Pase, alkaline phosphatase ALL-DB, alloxan-induced diabetic AMCV, artichoke mottled crinkle virus AMP, adenosine 5 -monophosphate 5 -AMP, adenosine 5 -monophosphate AMPA-R, AMPA-receptor AMPK, AMP-dependent protein kinase AMPKK, AMP-dependent protein kinase kinase... 

Routine laboratory tests may help to identify secondary hypertension. Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. Protein, blood cells, and casts in the urine may indicate renovascular disease. Some laboratory tests are used specifically to diagnose secondary hypertension. These include plasma norepinephrine and urinary metanephrine concentrations for pheochromocytoma, plasma and urinary aldosterone concentrations for primary aldosteronism, and plasma renin activity, captopril stimulation test, renal vein renins, and renal artery angiography for renovascular disease. 

Protein kinase C also has an important role in hormone and neurotransmitter release. For example, activated protein kinase C augments catecholamine release from the adrenal medulla, aldosterone secretion from the adrenal cortex, and acetylcholine release from the caudate nucleus. Furthermore, protein kinase C-elic-ited hormone and neurotransmitter release augment Ca -induced release mechanisms. 

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