Aldosterone and thyroid hormone modulation of ?1-, ?1-mRNA, and Na,K-Pump sites in rabbit distal colon epithelium. Evidence for a novel mechanism of escape from the effect of hyperaldosteronemia

Abstract

Aldosterone and thyroid hormone regulation of Na,K-pump biosynthesis has been examined in the distal colon epithelium of rabbits. Qualitative analysis of alpha-subunit isoform distribution (alpha 1, alpha 2, alpha 3) detected only the alpha 1-mRNA in the distal colon epithelium and outer renal medulla, while all three isoforms were observed in rabbit brain. A low-sodium diet led to a rise in serum aldosterone from 0.6 nM to 1.4-1.9 nM and an increase of alpha 1-mRNA to 162%, beta 1-mRNA to 120%, and the number of Na,K-pump units as determined by specific [3H]-ouabain binding to 182% of control by the second day of the diet. While aldosterone levels remained elevated, a spontaneous decrease in serum levels of T3 and T4 to 50-60% of control from the third day of the diet was followed by downregulation of beta 1-mRNA to 55-67%, alpha 1-mRNA to 63-105%, and of [3H]-ouabain binding to 103% of control, suggesting that a reduced rate of synthesis of the beta 1-subunit is rate limiting for Na,K-pump biosynthesis. Substitution with T3 (10 micrograms/kg) at the seventh day with transient restoration of serum T3 to control levels, led to rapid accumulation of beta 1-mRNA to 152%, of alpha 1-mRNA to 135%, and of the number of Na,K-pump units to 153% of control. This is consistent with thyroid hormone having a permissive role for the aldosterone stimulation of Na,K-pump biosynthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of inactivation of the action of aldosterone on collecting duct by TGF-β

“…1) is consistent with our previous results demonstrating an increase in ouabain binding after GC or MC exposure (18). Similar increases in ouabain binding occur in the colon of rabbits fed a low-NaCl diet (40) or in aldosterone-treated A6 cells (2). The results support a general model where steroids increase transcription of one or more of the Na ϩ -K ϩ -ATPase subunits (albeit modestly), increase pump synthesis (10), and insert more pumps on the basolateral membrane.…”

“…Glucocorticoid hormone, but not aldosterone, acutely increases the ␣ 1 -subunit of Na ϩ -K ϩ -ATPase mRNA levels in colon of normal rats (9), and aldosterone infusion restores the modest reduction in the ␣ 1subunit of Na ϩ -K ϩ -ATPase mRNA produced by adrenalectomy (7). A low-NaCl diet increases modestly the mRNA abundance of the ␣ 1 -and ␤ 1 -subunits of Na ϩ -K ϩ -ATPase in colon (40). Neither adrenalectomy nor aldosterone has more than a modest effect on Na ϩ -K ϩ -ATPase mRNA of the CCD (7).…”

Mechanisms of sodium pump regulation

“…Corticosteroid-mediated increases in protein synthesis of sodium pumps may be dependent on changes in cytoplasmic Na ϩ concentrations, as illustrated by abrogation of the effects in the presence of blockers of Na ϩ transport (156,169,242). In addition, corticosteroid effects may be facilitated by the thyroid hormone triiodothyronine (T3) in mammals (349), but not in amphibians (137). Interestingly, longterm stimulation of the sodium pump by aldosterone is abrogated by inhibitors of the protein phosphatase calcineurin in cultured Xenopus kidney (A6) cells (285).…”

Quantification and distribution of Ca2+-activated maxi K+channels in rabbit distal colon

“…To stimulate the distal colon epithelium in vivo, rabbits were kept on a low-Na ϩ diet consisting of pearl barley and distilled water for up to 7 days. This procedure is known to markedly enhance the endogenous secretion of aldosterone, resulting in an increase in plasma aldosterone levels of more than threefold compared with control levels (43).…”