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Acidosis inhibits 1,25‐(OH) 2 D 3 but not cAMP production in response to parathyroid hormone in the rat
Author(s) -
Ro HeungKyu,
Tembe Vrishali,
Krug Thomas,
Yang PoYao J.,
Bushinsky David A.,
Favus Murray J.
Publication year - 1990
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.5650050311
Subject(s) - endocrinology , medicine , parathyroid hormone , forskolin , acidosis , metabolic acidosis , tubule , chemistry , kidney , ammonium chloride , biology , calcium , stimulation , organic chemistry
Parathyroid hormone (PTH) is a major activator of renal proximal tubule 25‐hydroxyvitamin D 3 ‐1‐hydroxylase (1‐OHase). Chronic metabolic acidosis (CMA) inhibits 1‐OHase and reduces circulating 1,25‐dihydroxyvitamin D 3 [1,25‐(OH) 2 D 3 ] levels in rats fed a low‐Ca diet (LCD, 0.002% Ca). To examine the cellular mechanism whereby CMA inhibits 1‐OHase, PTH‐dependent renal 1‐OHase activity and cAMP were measured in proximal tubules isolated from rats fed LCD for 14 days and made acidotic by the addition of 1.5% ammonium chloride to the drinking water. Serum 1,25‐(OH) 2 D 3 and proximal tubule 1‐OHase activity and cAMP content were lower in acidotic rats. hPTH‐(1–34) (10 −7 M) in vitro increased cAMP content to equivalent concentrations in tubules from rats with CMA and from nonacidotic controls; however, PTH increased 1‐OHase activity only in tubules from nonacidotic animals. Although forskolin increased tubule cAMP content to equivalent levels in tubules from acidotic and nonacidotic rats, 1‐OHase activity declined in tubules from nonacidotic rats and remained suppressed in acidotic tubules. The results suggest that chronic metabolic acidosis inhibits the PTH activation of 1‐OHase through alteration of one or more steps in a cAMP‐independent messenger system. PTH and forskolin can increase cAMP production by acidotic and nonacidotic proximal tubules; however, 1‐OHase activity is not restored to normal in acidotic tubules and nonacidotic tubule 1‐OHase may be inhibited.