Acidosis inhibits 1,25-(OH)2D3 but not cAMP production in response to parathyroid hormone in the rat.
Parathyroid hormone (PTH) is a major activator of renal proximal tubule 25-hydroxyvitamin D3-1-hydroxylase (1-OHase). Chronic metabolic acidosis (CMA) inhibits 1-OHase and reduces circulating 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] 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)2D3 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.
Ro
H K
HK
Department of Medicine, University of Chicago Pritzker School of Medicine, IL 60637.
Tembe
V
V
Krug
T
T
Yang
P Y
PY
Bushinsky
D A
DA
Favus
M J
MJ
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D002117:Calcitriol / Q000096:biosynthesis*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011863:Radioimmunoassay; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains
D010281:Parathyroid Hormone; D005576:Colforsin; D000242:Cyclic AMP; D002117:Calcitriol