Acidosis inhibits 1,25-(OH)2D3 but not cAMP production in response to parathyroid hormone in the rat

J Bone Miner Res. 1990 Mar;5(3):273-8. doi: 10.1002/jbmr.5650050311.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acidosis / metabolism*
  • Animals
  • Calcitriol / biosynthesis*
  • Colforsin / pharmacology
  • Cyclic AMP / biosynthesis*
  • In Vitro Techniques
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Parathyroid Hormone / pharmacology*
  • Radioimmunoassay
  • Radioligand Assay
  • Rats
  • Rats, Inbred Strains

Substances

  • Parathyroid Hormone
  • Colforsin
  • Cyclic AMP
  • Calcitriol