Non-genomic effects of aldosterone: new actions and questions

doi:10.1016/j.tem.2004.08.002

Trends in Endocrinology & Metabolism

Volume 15, Issue 8, October 2004, Pages 353-354

https://doi.org/10.1016/j.tem.2004.08.002 Get rights and content

Although the classical actions of aldosterone are mediated through genomic pathways, there is a growing recognition of important nongenomic responses to aldosterone. New data are presented from two laboratories showing a nongenomic effect of aldosterone to activate protein kinase C (PKC) in heart and kidney. Among the actions of PKC is the stimulation of transcription factors, raising the question of whether there is an inter-relationship of nongenomic with genomic influences – aldosterone induced nongenomic effects might modulate genomic effects. This expanded role of aldosterone will require exploration in future studies.

Section snippets

Non-genomic influences genomic?

A question arises from consideration of the intermediary role of PKCε – to what extent are genomic actions of aldosterone dependent on its non-genomic actions? An increase in PKC activity results in activation of transcription factors, and thus non-genomic influences obviously give rise to at least some genomic regulation (Figure 1). Could the non-genomic action of aldosterone lead to a modulation of aldosterone's genomic action, functioning either to enhance or mitigate the genomic response?

Conclusion

Non-genomic influences of aldosterone are becoming more widely recognized. This is in part a result of the growing awareness of the effects of aldosterone on non-epithelial sites (e.g. heart and kidney) in which non-genomic actions could partner with genomic actions. The non-genomic story has seemingly been stifled by the elusive nature of the membrane receptor. However it would seem that there is much to learn without knowing the nature of ‘the receptor’ as demonstrated by the papers of

Acknowledgements

Support provided by NIH grants R01-HL-35795 and RO1-HL-67360 and by the Department of Veterans Affairs.

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Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C
Endocrinology
(2004)

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Mineralocorticoid Action in the Aldosterone-Sensitive Distal Nephron
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Regulation of epithelial Na<sup>+</sup> channels (ENaC) by methylation: A novel methyltransferase stimulates ENaC activity
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Citation Excerpt :
In this classic genomic model, the early effects of aldosterone to stimulate ENaC activity may be due to trafficking of already synthesized channel subunits, under the influence of the aldosterone-induced protein SGK-1 (27, 29), or to a direct effect on channel open probability (3). Early and rapid non-genomic effects of aldosterone have also been described in a number of tissues and cell types that are not related to binding of the classic mineralocorticoid receptor, and among these effects are direct, rapid (<2 min) activation of ENaC (5–8). In the CCD cells that we have used in these studies, all the effects of aldosterone appear to be mediated via the classic, genomic pathway (17), although it seems clear that the early phase of stimulation of ENaC activity is not fully explained by activation of SGK-1, suggesting that other pathways may be involved (8, 29, 30).
Aldosterone acts to increase apical membrane permeability by activation of epithelial Na⁺ channels (ENaC). We have previously shown that aldosterone activates ENaC early in the course of its action by stimulating the methylation of the β subunit of this heteromeric channel in A6 cells. Aldosterone also stimulates the expression and methylation of k-ras in A6 cells. To determine whether aldosterone-stimulated methylations are seen in mammalian cells, we examined the effect of aldosterone on methylation and ras activation in a continuous line of cultured epithelial cells derived from mouse cortical collecting duct (CCD) and determined that β mENaC is a substrate for methylation by an enzyme contained in CCD cells. Aldosterone stimulated protein base labile methylation in CCD cells. Aldosterone stimulated Na⁺ transport in CCD cells within 1 h of addition and without an increase in cellular amount of any ENaC subunits over the first 4 h. Inhibition of methylation, using the inhibitor 3-deaza-adenosine, blocked the stimulation of Na⁺ transport induced by aldosterone at early time points (1–4 h) without affecting cellular amounts of any ENaC subunits. In contrast to 3-deaza-adenosine (3-DZA), which inhibits all methylation reactions, specific inhibitors of small G-protein methylation or prenylation had no effect on the early aldosterone-induced current. Overexpression of isoprenylcysteine carboxylmethyltransferase (PCMTase), the enzyme that methylates ras, had little effect on basal transport but enhanced aldosterone-stimulated transport in A6 cells. Overexpression of PCMTase in CCD cells had no effect on either basal or aldosterone-stimulated transport. Moreover PCMTase had no effect on ENaC activity when co-expressed in Xenopus oocytes. Aldosterone had no effect on either message or protein levels of k-ras in CCD cells. Searching a mouse kidney library, we identified a methyltransferase that stimulates ENaC activity in Xenopus oocytes without affecting surface expression of ENaC. Our results demonstrate that aldosterone stimulates protein methylation in CCD cells, and this is required for expression of the early transport response. In CCD cells this effect is not mediated via methylation of ras, which is not induced by aldosterone in these cells, and the enzyme that methylates ras has no direct effect on ENaC activity. β ENaC is a substrate for methylation in CCD cells. A novel methyltransferase that stimulates ENaC directly has been identified in CCD cells.
Growth of embryonic renal parenchyme at the interphase of a polyester artificial interstitium
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The construction of an artificial kidney module by tissue engineering or the application of cell-based therapies for the treatment of renal failure requires exact information regarding the cellbiological mechanisms of parenchyme development in combination with different kinds of biomaterials. To learn more about these processes tissue cultures are frequently used experimental tools. However, apart from experiments with early kidney anlagen there is a lack of suitable in-vitro models regarding the generation and long-term maintenance of renal tubules. In the present paper we like to demonstrate an advanced culture technique, which allows to generate tubular elements derived from renal stem cells. For the growth of tubules it is essential to fine-tune the interface between the embryonic tissue and the dead fluid space within a perfusion culture container by offering a polyester artificial interstitium. Culture was performed in IMDM supplemented with hormones and growth factors but using serum-free conditions over 14 days. Formation of tissue was then analysed by immunohistochemistry and two-dimensional (2D) electrophoresis. Culture in pure IMDM leads to a complete loss of tissue formation. In contrast, application of aldosterone (A) induces the development of numerous polarised tubules. Surprisingly, addition of epidermal growth factor (EGF), a cocktail of insulin, transferrin and selenium (ITS), retinoic acid (RA), cholecalciferol (VitD₃) or bovine pituitary extract (BPT) does not further improve development of tubules, but leads to intensive cell clustering and a decrease of tubule formation. 2D Western blots of developing tissue probed with soybean agglutinin (SBA) reveal a unique pattern of newly detected proteins. It is found that growth factors do not support but abolish protein spots upregulated by aldosterone. It remains to be investigated, which cellbiological effect stimulates the embryonic cells to develop tubules in competition to cell clusters at the interphase of an artificial interstitium.
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Trends in Endocrinology & Metabolism

Research FocusNon-genomic effects of aldosterone: new actions and questions

Section snippets

Non-genomic influences genomic?

Conclusion

Acknowledgements

Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium

Br. J. Pharmacol.

Nongenomic stimulation of vacuolar H+-ATPases in intercalated renal tubule cells by aldosterone

Proc. Natl. Acad. Sci. U. S. A.

Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C

Endocrinology

Research Focus
Non-genomic effects of aldosterone: new actions and questions