Rapid stimulation of cyclic AMP production by aldosterone in rat inner medullary collecting ducts

Abstract

Aldosterone stimulates sodium transport in the inner medullary collecting duct (IMCD) via the classic genomic pathway, but it is not known whether it also acts via a rapid, non-conventional pathway in this part of the nephron. The IMCD regulates the final sodium content of urine and expresses vasopressin receptors coupled to adenylate cyclase. The recently reported rapid, nongenomic actions of aldosterone have been associated mainly with an increase in intracellular Ca 2+; however, it has also been shown to stimulate cAMP generation. Thus the aim of this study was to determine whether aldosterone stimulates rapid generation of cAMP in isolated IMCD segments. IMCD segments were microdissected from Sprague-Dawley rat kidneys and incubated at 37 C for 4 min with aldosterone (10 12 to 10 6 M), vasopressin (10 12 to 10 6 M), or a combination of hormones in the presence of a phosphodiesterase inhibitor. cAMP was measured by radioimmunoassay. While corticosterone and dexamethasone were ineffective, aldosterone stimulated a dose-dependent increase in cAMP within 4 min (P<0·05). This action of aldosterone was not inhibited by the MR antagonist spironolactone. Co-incubation of aldosterone with vasopressin resulted in a further increase in cAMP generation above that induced by the neurohypophysial hormone alone. Aldosterone-mediated cAMP generation was not inhibited by a vasopressin V 1 or V 2 receptor antagonist. These data support a novel and rapid, non-genomic effect of aldosterone in IMCD. Aldosterone does not apparently interact with the vasopressin receptor to stimulate cAMP generation.

Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

“…49 -52 It has been reported that some of the nongenomic effects of aldosterone may be induced through the modulation of angiotensin II-, vasopressin-, and EGF-dependent signaling pathways. 51,[53][54][55][56] The results of our study demonstrate, also for the first time, that the addition of aldosterone rapidly enhances the level of IGF-IR phosphorylation that triggers intracellular signaling, leading to the up-regulation of elastin mRNA expression in cardiac fibroblast cultures ( Figures 5 and 6). These data are to some extent consistent with recently published observations showing that a very highly elevated level of aldosterone (1.5 mol/L) transactivates the IGF-IR in renal epithelial cells.…”

Nongenomic Actions of Aldosterone on the Renal Tubule

“…70,71 Last, but of significant interest, aldosterone at physiological concentrations caused a rapid (Ͻ4-minute), 2-to 3-fold increase in intracellular cAMP in microdissected rat inner medullary collecting ducts. 55 This increase occurred independent of the V 1 and V 2 vasopressin receptors and was additive to increases in cAMP induced by arginine vasopressin. These findings raise the possibility that aldosterone may act via nongenomic mechanisms to regulate a number of cAMPdependent collecting duct functions, such as H 2 O absorption via aquaporin-2 H 2 O channels and urea absorption via UT-A urea transporters.…”

“…Whether aldosterone influences NKCC1 in the kidney has not been explored. Finally, aldosterone affects a number of signaling pathways in renal cells in addition to those listed in the Table, including cAMP/protein kinase A (PKA), 55,56 calcineurin, 57 Src, 58 and heat shock proteins. 57,58 Their possible significance for nephron function is considered below.…”

“…57,58 Of note, the transcriptionindependent activation of calcineurin by aldosterone in the CCD requires 30 minutes to develop, presumably because of time required for disassociation of the heat shock protein-MR complex. 57 The longer time course for activation of calcineurin compared with that for other nongenomic signals, such as cAMP and ERK (Ͻ5 minutes), 26,55,65 may reflect aldosterone actions mediated through different receptors and/or differing complexities of aldosterone-induced signaling pathways. The significance of nongenomic signaling via the MR for aldosterone-induced regulation of epithelial transport remains to be established.…”

“…ERK and cAMP, which are activated rapidly by aldosterone in a variety of renal cells, 26,37,55,56,65,106 can increase the activity and expression of the early aldosteroneinduced protein SGK1, [107][108][109] which regulates multiple ion transport proteins in renal cells, including ENaC, ROMK, and the Na-Cl cotransporter. 5,6,40 The cAMP/PKA pathway also may regulate ENaC independently of SGK through phosphorylation and inhibition of Nedd4-2, which results in increased expression of ENaC in the cell membrane.…”