LOSS OF PARATHYROID HORMONE-STIMULATED 1,25-DIHYDROXYVITAMIN D-3 PRODUCTION IN AGING DOES NOT INVOLVE PROTEIN-KINASE-A OR PROTEIN-KINASE-C PATHWAYS

Intestinal calcium absorption declines with aging as a result of decre ased renal 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] biosynthesis. A t least part of the decline in 1,25-(OH)(2)D-3 may be due to acquired resistance to parathyroid hormone (PTH) stimulation of renal 25-hydrox yvitamin D1-hydroxylase (1-OHase) activity. To test whether aging rats can increase 1,25-(OH)(2)D-3 production in response to PTH, male rats of the same litter were fed a normal Ca diet and were sacrificed at 1 75-225 g (young rats) or 3 months later at 350-425 g (aging rats). At sacrifice, basal serum 1,25-(OH)(2)D-3 levels (88 +/- 16 versus 49 +/- 8 pg/ml, P < 0.05) and in vitro renal proximal tubule 1-OHase activit y (178 +/- 15 versus 77 +/- 5 pmol/mg protein/5 minutes, n = 6, P < 0. 001) were lower in aging animals. rPTH-(134) (10(-11) or 10(-7) M) inc reased in vitro 1,25-(OH)(2)D-3 secretion by perifused renal proximal tubules from young but not aging rats. For young and aging rats, rPTH- (1-34) (10(-7) M) increased proximal tubule cAMP-dependent protein kin ase (PKA) activity, and lower concentrations (10(-11) M) stimulated tr anslocation of protein kinase C (PKC) activity from cytosolic to solub le membrane proximal tubule cell fractions. The results of this study show that PTH activation of 1,25-(OH)(2)D-3 production may involve bot h signaling pathways, with the PKC pathway responsive to lower concent rations of the hormone. The acquired resistance to PTH stimulation of 1,25-(OH)(2)D-3 production in aging appears not to involve the hormona l activation of PKA or PKC.