R. Buffenstein et al., VITAMIN-D HYDROXYLASES AND THEIR REGULATION IN A NATURALLY VITAMIN-D-DEFICIENT SUBTERRANEAN MAMMAL, THE NAKED MOLE-RAT (HETEROCEPHALUS-GLABER), Journal of Endocrinology, 138(1), 1993, pp. 59-64
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.