EDITORIAL FOCUS
Focus on "Aldosterone responsiveness of A6 cells is restored by cloned rat mineralocorticoid receptor"

Charles O. Watlington

Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0145

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A6 CELLS HAVE BECOME a standard model epithelium for studies of the action of steroids on active Na+ transport (3, 6) and are the first cell culture model system widely used for this purpose. These cells have "tight" tight junctions that allow the convenient measurement of active Na+ transport and ion flux by Ussing chamber techniques. Indeed, A6 cells exhibit basal active Na+ transport [short-circuit current (SCC)] that is stimulated by mineralo- and glucocorticoids with a time course of action suggesting typical steroid receptor-mediated transcription alteration (7).

A long-existing mystery in research on corticosteroid action in A6 cells is the finding that most of the induced SCC is mediated by the glucocorticoid receptor (GR) (5, 7), despite the fact that typical mineralocorticoid receptors (MR) (2) are, in fact, present in A6 cells. Even the action of aldosterone on SCC in A6 cells appears to be GR mediated (7). The article in focus (Ref. 1; see p. C39 in this issue) is the first published article demonstrating MR-mediated corticosteroid action in A6 cells. These findings of Chen et al. (1) represent a breakthrough and a report on a much needed system (the A6 cell line in which the rat MR is stably transfected) to study steriod-induced MR-mediated action on active Na+ transport. These authors are to be applauded for this benchmark report.

An interesting speculation provoked by this report is why A6 and, indeed, cultured cell lines in general do not seem to use MR to mediate their transport response to steroids. The current report demonstrates that such a response, presumably mediated by binding to the same hormone response elements as GR, can be induced. These findings, the authors point out, are inconsistent with the data that a defect in aldosterone entry or metabolism accounts for the lack of MR mediation in wild-type A6. Their speculation is that it is related to the extremely small number of MR present in A6 or that MR may be suppressed during establishment of continuous lines. The only other report of MR-mediated transport stimulation in A6 cells suggests that there may be metabolism of steroids to products with low affinity for MR (4). This possibility could be directly tested in a model that has abundant MR, such as that developed here (1). The mechanisms of transport stimulation after receptor binding could also be addressed. A6 steroid-induced SCC has been taken as a model of mammalian mineralocorticoid action even though mediated via GR. The direct comparison of MR- and GR-stimulated SCC and the biochemical intermediaries may now be made in the same cell line.

One intriguing possibility is that corticosteroid-induced SCC is via GR/MR heterodimer binding to the appropriate hormone-responsive element upstream of the genes to be regulated in A6 cells. The rat MR-transfected A6 cell line, reported here by Chen et al. (1), should be an excellent tool for evaluation of the heterodimer hypothesis. Also, transient or stably tranfected lines are a powerful tool for examining the activity of mutant receptors on SCC, thus producing more information about this "essential physiological response," as noted by these authors.

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1.   Chen, S.-Y., J. Wang, W. Liu, and D. Pearce. Aldosterone responsiveness of A6 cells is restored by cloned rat mineralocorticoid receptor. Am. J. Physiol. 274 (Cell Physiol. 43): C39-C46, 1998[Abstract/Free Full Text].

2.   Claire, M., B. Machard, M. Lombes, M. E. Oblin, J. P. Bonvalet, and N. Farman. Aldosterone receptors in A6 cells: physicochemical characterization and autoradiographic study. Am. J. Physiol. 257 (Cell Physiol. 26): C665-C677, 1989[Abstract/Free Full Text].

3.   Johnson, J. P. Cellular mechanisms of action of mineralocorticoid hormones. Pharmacol. Ther. 53: 1-29, 1992[Medline].

4.   Johnson, J. P., M. D. Rokaw, M. E. West, and D. J. Morris. Inhibitors of 11beta hydroxysterioid dehydrogenase (11beta -HSD) enhance corticosterone-stimulated Na+ transport in A6 cells (Abstract). J. Am. Soc. Nephrol. 6: 738, 1995.

5.   Schmidt, T. J., R. F. Husted, and J. B. Stokes. Steroid hormone stimulation of Na+ transport in A6 cells is mediated via glucocorticoid receptors. Am. J. Physiol. 264 (Cell Physiol. 33): C875-C884, 1993[Abstract/Free Full Text].

6.   Verry, F. Transcriptional control of sodium transport in tight epithelia by adrenal steroids. J. Membr. Biol. 144: 93-110, 1995[Medline].

7.   Watlington, C. O., F. M. Perkins, P. J. Munson, and J. S. Handler. Aldosterone and corticosterone binding and effects on Na+ transport in cultured kidney cells. Am. J. Physiol. 242 (Renal Fluid Electrolyte Physiol. 11): F610-F619, 1982[Medline].


AJP Cell Physiol 274(1):C38-C38
0363-6143/98 $5.00 Copyright © 1998 the American Physiological Society




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