VITAMIN-D HYDROXYLASES AND THEIR REGULATION IN A NATURALLY VITAMIN-D-DEFICIENT SUBTERRANEAN MAMMAL, THE NAKED MOLE-RAT (HETEROCEPHALUS-GLABER)

The vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is genera ted by a series of hydroxylation steps in the liver and kidneys. We in vestigated whether naturally vitamin D-deficient subterranean mammals (naked mole rats, Heterocephalus glaber) employ the same enzymatic pat hways, and whether these are regulated in a similar manner to that est ablished for other mammals. Vitamin D3-25-hydroxylase in the liver and both 25-hydroxyvitamin D3-1-hydroxylase and 25-hydroxyvitamin D3-24 h ydroxylase (1-OHase and 24-OHase) in the kidney were detectable in mol e rats. As expected for vitamin D-deficient mammals, the 1-OHase activ ity predominated over the 24-OHase. After mole rats received a supraph ysiological supplement of vitamin D3, 1-OHase activity was suppressed and 24-OHase activity was enhanced. Irrespective of vitamin D status, forskolin (a protein kinase A activator) and dibutyryl cyclic AMP did not alter the activity of either 1-OHase or 24-OHase. These findings s uggest that the response of renal hydroxylases to parathyroid hormone was blunted. Phorbol esters, 12-O-tetradecanoylphorbol 13-acetate (TPA ) and 1-oleoyl-2-acetylglycerol (OAG) (protein kinase C activators), s uppressed 1-OHase activity. 24-OHase activity was induced by TPA but n ot by OAG. These effects were similar to those illicited by vitamin D3 supplementation but were additive in that they increased the response s shown in vitamin D-replete mole rats. These data confirm that natura lly vitamin D-deficient mole rats can convert vitamin D3 to the hormon e, 1,25(OH)2D3. Furthermore, the enzymes 1-OHase and 24-OHase present in the kidneys of these mammals are regulated independently by 1,25(OH )2D3 and protein kinase C-mediated pathways of intracellular signallin g, but are not regulated by the cyclic AMP-protein kinase A signal tra nsduction pathway.