Insulin-like growth factor-I regulation of renal 25-hydroxyvitamin D-1-hydroxylase activity.
Controversy exists regarding the role of GH and insulin-like growth factor-I (IGF-I) in the modulation of calcitriol production. While their administration increases serum levels of 1,25-dihydroxyvitamin D, the mechanism remains unknown. Investigations have also implicated GH as a causal factor underlying renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity [1(OH)ase] secondary to phosphate depletion. Thus, we investigated the effects of IGF-I on 1(OH)ase and the relationships between these actions and those of phosphate depletion. Our studies indicate that IGF-I administration to normal mice results in a dose-dependent (0-10 micrograms/h) increase in 1(OH)ase with maximum effects evident after 24 h, independent of changes in serum calcium, phosphorus, and glucose levels. Similarly, hormone administration to phosphate-depleted mice increases enzyme activity (6.06 +/- 0.96 vs. 13.97 +/- 1.67 fmol/mg.min) but to a level significantly greater than that achieved in normals (2.72 +/- 0.4 vs. 5.01 +/- 0.56 fmol/mg.min). Furthermore, the response represents an additive increment of the effects elicited by maximum doses of IGF-I and phosphate depletion, suggesting that the hormone- and phosphate-dependent enzyme stimulation occur by different mechanisms. Thus, our data establish that IGF-I stimulates renal 1(OH)ase activity in a time- and dose-dependent fashion. However, they do not support the hypothesis that IGF-I modulates the effects of phosphate-depletion on 1(OH)ase activity. Regardless, the documentation that IGF-I stimulates enzyme function provides an explanation for many observed physiological states associated with concomitant alterations of hormone levels and calcitriol production.
Nesbitt
T
T
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Drezner
M K
MK
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000097:blood; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010710:Phosphates / Q000172:deficiency; D010758:Phosphorus / Q000097:blood
D001786:Blood Glucose; D010710:Phosphates; D010758:Phosphorus; D007334:Insulin-Like Growth Factor I; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002118:Calcium