Departments of 1 Medicine and 2 Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555
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ABSTRACT |
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Rapid actions of aldosterone
that are independent of transcription and translation have been
described in a variety of cells; however, whether nongenomic pathways
mediate aldosterone-induced regulation of renal tubule transport has
not been determined. We report here that aldosterone induces rapid
(<3.5 min) inhibition of HCO 0.6 nM) and is not affected by pretreatment
with actinomycin D (12.5 µg/ml), cycloheximide (40 µg/ml), or
spironolactone (10 µM). The glucocorticoids dexamethasone, cortisol,
and corticosterone (1 or 500 nM) did not affect HCO
-hydroxysteroid dehydrogenase activity. The inhibition by
aldosterone is additive to inhibition by angiotensin II and
vasopressin, indicating that these factors regulate MTAL transport
through distinct pathways. These results demonstrate that aldosterone
inhibits HCO
kidney; glucocorticoids; acid-base balance; mineralocorticoid
receptor; 11-hydroxysteroid dehydrogenase
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INTRODUCTION |
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ALDOSTERONE PLAYS AN
IMPORTANT role in the regulation of Na+,
K+, and acid-base balance through its effects on renal
electrolyte excretion. Aldosterone influences ion transport in
multiple nephron segments, including the collecting duct, thick
ascending limb, and distal convoluted tubule (1, 11, 21, 31, 39,
45). In segments of the collecting duct, aldosterone acts
directly to stimulate Na+ absorption, K+
secretion, and H+ secretion (1, 21, 39, 42).
In collecting duct principal cells and other
Na+-reabsorbing epithelia, aldosterone stimulates
Na+ absorption by inducing gene transcription and the
subsequent translation of new proteins. The aldosterone-induced
proteins lead to increased Na+ absorption by increasing the
activity and number of apical membrane Na+ channels (ENaC)
and basolateral membrane Na+-K+-ATPase subunits
(34, 39, 46). The transcriptional regulation of
Na+ absorption, K+ secretion, and
H+ secretion by aldosterone occurs after a latent period of
45 min-2 h and is mediated through binding of aldosterone to the
classic (type 1) mineralocorticoid receptor (1, 21, 39, 42,
46). This receptor has equal affinity for aldosterone and
glucocorticoids (cortisol and corticosterone) in cytosol preparations
(15, 16). Specificity of aldosterone regulation in
epithelial target tissues is achieved through the action of the enzyme
11-hydroxysteroid dehydrogenase type 2 (11
-HSD2), which
metabolizes cortisol and corticosterone to inactive analogs that do not
bind the mineralocorticoid receptor (15, 17, 39).
In recent years, evidence has accumulated for rapid cellular actions of aldosterone that are not dependent on nuclear transcription or protein synthesis and occur through receptors other than the classic mineralocorticoid receptor (13, 28, 52). A prominent nongenomic effect of aldosterone is stimulation of Na+/H+ exchange activity. This stimulation is observed in a variety of tissues, including colonic epithelial cells and renal cell lines, and is mediated through activation of PKC (12, 13, 20, 28, 29, 33, 53). The rapid action of aldosterone on Na+/H+ exchange has been proposed to play a role in the regulation of epithelial Na+ absorption, intracellular pH-induced regulation of K+ channels, processing of aldosterone-induced proteins, and the rapid (5-10 min) effect of aldosterone on renal Na+ and K+ excretion in vivo (13, 18, 20, 28, 29, 52, 53). At present, however, it has not been determined whether nongenomic pathways are relevant to the regulation of transepithelial transport by aldosterone in the kidney. In addition, it is unknown whether aldosterone regulates Na+/H+ exchange activity or its related functions in mammalian renal tubules.
The medullary thick ascending limb (MTAL) of the loop of Henle performs
a number of important renal transport functions, including reabsorption
of NaCl that is essential for the maintenance of Na+
balance and the excretion of a dilute or concentrated urine
(35). The MTAL also participates in the regulation of
acid-base balance by reabsorbing most of the filtered
HCO
The present study was designed to examine directly the acute effects of
aldosterone on HCO
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METHODS |
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MTALs from male Sprague-Dawley rats (50-100 g; Taconic,
Germantown, NY) were isolated and perfused in vitro as previously described (22, 25). The rats had free access to standard
chow (NIH 31 diet, Ziegler) and distilled H2O up to the
time of experiments. Tubules were dissected from the inner stripe of
the outer medulla at 10°C in control bath solution (see below),
transferred to a bath chamber on the stage of an inverted microscope,
and mounted on concentric glass pipettes for perfusion at 37°C. In
all experiments, the lumen and bath solutions contained (in mM) 146 Na+, 4 K+, 122 Cl, 25 HCO
The protocol for study of transepithelial HCO1 · mm
1. One to
three 10-min tubule fluid samples (sample volume 10 nl) were then
collected for each period (initial, experimental, and recovery). The
tubules were allowed to reequilibrate for 5-10 min after an
experimental agent was added to or removed from the bath solution. In
some experiments, longer treatment periods were used, as described in
RESULTS. In one series of experiments, the luminal flow
rate was increased to ~3.2
nl · min
1 · mm
1, the
collected fluid volume was decreased to 5 nl, and sample collection was
begun within 1 min after addition of aldosterone to the bath solution.
With these modifications, samples could be obtained within 3.5 min of
aldosterone exposure (see RESULTS). The absolute rate of
HCO
1 · mm
1) was
calculated from the luminal flow rate and the difference between total
CO2 concentrations measured in perfused and collected fluids (22). Total CO2 concentrations were
measured by microcalorimetry using a picapnotherm, as previously
described (22). An average HCO
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RESULTS |
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Aldosterone rapidly inhibits
HCO1 · mm
1
(P < 0.001; Fig. 1A). The
inhibition was complete within 10-15 min of exposure to
aldosterone (the time required for one sample collection), sustained
for up to 100 min, and reversible. The aldosterone-induced decrease in
HCO
0.6 nM (Fig.
1B). The HCO
Effect of furosemide.
One possible explanation for the inhibition of HCO cotransport
activity could increase intracellular Na+ activity, thereby
reducing the driving force for apical Na+/H+
exchange and inhibiting HCO
4 M furosemide to inhibit
Na+-K+-2Cl
cotransport and net
NaCl absorption, addition of 1 nM aldosterone to the bath decreased
HCO
1 · mm
1
(P < 0.001; n = 3). Thus aldosterone
inhibits HCO
Effects of actinomycin D and cycloheximide.
MTALs were bathed with the transcription inhibitor actinomycin D (12.5 µg/ml) for 90 min or the protein synthesis inhibitor cycloheximide
(40 µg/ml) for 120 min before the addition of aldosterone. Similar or
less extensive treatments with these agents have been shown to block
transcription and protein synthesis in multiple systems, including
renal epithelial cell lines (8, 10, 30, 33, 37), and to
inhibit genomic regulation of HCO1 · mm
1
(P < 0.025; Fig. 2A). In the presence of
cycloheximide, 1 nM aldosterone decreased
HCO
1 · mm
1
(P < 0.01, Fig. 2B). In both cases, the
aldosterone-induced inhibition was rapid (<15 min) and reversible.
Thus the inhibition of HCO
Effect of spironolactone.
MTALs were bathed initially for 100 min with 10 µM spironolactone, a
competitive antagonist of the mineralocorticoid receptor. In the
presence of spironolactone, addition of 1 nM aldosterone to the bath
decreased HCO1 · mm
1
(P < 0.001; Fig. 3). Thus the inhibition by
aldosterone is not mediated through the classic mineralocorticoid receptor.
Steroid specificity and effect of carbenoxolone.
To determine the specificity of aldosterone action, we examined the
effects of glucocorticoids. Addition of either dexamethasone or
cortisol (1 or 500 nM) to the bath for up to 40 min had no effect on
HCO
Interaction of aldosterone with angiotensin II and vasopressin.
Angiotensin II and AVP inhibit HCO1 · mm
1
(P < 0.005; Fig. 6A). In the presence of
10
10 M AVP, 1 nM aldosterone decreased
HCO
1 · mm
1
(P < 0.01; Fig. 6B). Thus the inhibition of
HCO
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DISCUSSION |
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Aldosterone regulates Na+, K+, and net
acid excretion in the mammalian kidney by binding to nuclear receptors
and stimulating the production of transcriptionally induced regulatory
proteins (1, 21, 39, 42, 46). In recent years, rapid
effects of aldosterone on ion transport and signaling pathways that are not dependent on gene transcription or protein synthesis have been
described in multiple systems, including epithelial cells (13,
52). However, whether nongenomic pathways are relevant for
aldosterone-induced regulation of renal tubule function has not been
determined. The results of the present study demonstrate that
aldosterone inhibits HCO
Mineralocorticoid and glucocorticoid receptors are expressed in thick
ascending limbs (6, 11, 14, 43). At least two observations
indicate that the classic mineralocorticoid receptor does not mediate
the aldosterone-induced inhibition of HCO-HSD2 activity. The lack of effect of
cortisol, corticosterone, and dexamethasone on HCO
Membrane-bound receptors have been proposed to mediate specific,
nongenomic effects of aldosterone on the basis of several lines of
evidence: 1) radioligand-binding studies in plasma membranes from pig kidney identified specific, high-affinity aldosterone binding
sites exhibiting kinetic and pharmacological properties consistent with
the nongenomic actions of aldosterone on cell functions (9,
52); 2) rapid stimulation of
Na+/H+ exchange by aldosterone in Madin-Darby
canine kidney (MDCK) cells is elicited by using an aldosterone-albumin
conjugate that prevents aldosterone entry into the cells
(20); and 3) membrane receptors that mediate
rapid cellular effects have been partially characterized for other
steroid hormones, including vitamin D and estrogen (13, 38, 48,
52). In addition to membrane-bound receptors, nonclassic receptor mechanisms for steroids may include binding to enzymes or
signaling proteins, or the rapid activation of signal transduction pathways through binding to classic receptors (7, 13, 28, 38). Recent work suggests that PKC isoforms may act as specific aldosterone receptors (28); however, as discussed below,
PKC is unlikely to mediate rapid inhibition of HCO
Although the mechanism by which aldosterone inhibits
HCO
Rapid regulation of Na+/H+ exchange activity by
aldosterone in a variety of cell types is mediated through activation
of PKC (12, 20, 28, 33, 53). At least two lines of
evidence suggest that PKC does not mediate aldosterone-induced
inhibition of HCO
Rapid effects of aldosterone have been previously described in renal cells. In the mouse cortical collecting duct cell line M-1 and in MDCK cells, which share transport properties with collecting duct cells, aldosterone increased Na+/H+ exchange activity via nongenomic pathways involving Ca2+ and PKC, as noted above (20, 29). In principal cells isolated enzymatically from cortical collecting ducts, aldosterone induced a rapid increase in Na+ channel (ENaC) activity that was not blocked by spironolactone, consistent with nongenomic regulation (55). However, in the latter study, the stimulation of Na+ channel activity was induced with a pharmacological concentration of aldosterone, specificity of the transport effect for aldosterone was not established, and the transport stimulation was observed in principal cells from rabbits but not from rats (55). Thus the significance of nongenomic pathways for aldosterone-induced regulation of collecting duct Na+ transport remains to be determined. These studies suggest, however, that the collecting duct may be a target for nongenomic aldosterone regulation, in addition to the MTAL.
Previous information on regulation of thick ascending limb acid
secretion by aldosterone has been obtained from studies of adrenalectomized rats. Adrenalectomy reduced net HCO
We have suggested previously that the MTAL plays a key role in enabling
the kidney to maintain acid-base balance during changes in
Na+ and volume balance (23, 25). The results
of the present study identify nongenomic regulation by aldosterone as a
mechanism that may contribute to this process. Activation of the
renin-angiotensin-aldosterone system in response to Na+ and
extracellular fluid volume depletion promotes renal Na+
retention but also results in multiple transport effects that act
cooperatively to increase urinary net acid excretion and promote metabolic alkalosis. The latter include stimulation of
HCO
In addition to the physiological roles outlined above, the nongenomic
pathway for aldosterone identified here has other important physiological and clinical implications for renal function. A defect in
nongenomic pathway(s) may contribute to mineralocorticoid resistance in
cases of pseudohypoaldosteronism with no evidence of abnormality in the
mineralocorticoid receptor gene (16, 52). In addition, the
nongenomic pathway regulating MTAL function is highly aldosterone
selective. Thus this pathway may provide a mechanism for
mineralocorticoid specificity independent of 11-HSD2 activity,
mediate aldosterone-specific regulation of electrolyte transport or
other cell functions in nephron segments in which mineralocorticoid
receptor expression is low or absent, and lead to novel therapeutic
targets and strategies for modifying renal corticosteroid action.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-38217.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. W. Good, 4.200 John Sealy Annex, Univ. of Texas Medical Branch, 301 Univ. Blvd., Galveston, Texas 77555-0562 (E-mail: dgood{at}utmb.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
June 4, 2002;10.1152/ajprenal.00133.2002
Received 10 April 2002; accepted in final form 25 May 2002.
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