Page 138 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

128 ELECTROLYTE DISORDERS

regulation of placental calcium transport. 309 PTHrP is
PTHrP actions
also produced by the uterus, where it is important in per-
mitting relaxation of the smooth muscle of the muscularis
as the fetus grows. 565
Normal/ Normal/ Abnormal/
endocrine paracrine endocrine
VITAMIN D

• Fetal • Skin • Humoral Vitamin D (calciferol) is classified as a secosteroid hor-
parathyroid • Mammary glands hypercalcemia mone. 261 In tetrapods, the role of vitamin D via the
glands • Endocrine organs of malignancy
• Placenta • Muscle calcitriol-activated VDR has evolved into one dominated
• Lymphoid organs by calcium regulatory mechanisms, but the roles in prim-
• Kidneys itive species, including regulation of detoxification
• Bone enzymes, have commonly been retained in more evolved
• Brain 596,613
Figure 6-8 Actions of parathyroid hormone-related protein life forms. These pleiotropic actions of vitamin
330
(PTHrP). D include, among others, important roles as antiproli-
25
ferative and prodifferentiative mediators working in
part via control of DNA replication 164 and roles as
fetal placenta, 343 and the C-terminal region can inhibit immunomodulators, 238 including effects on glomerulo-
osteoclastic bone resorption. 181 nephritis 431 and encephalitis. 205 A role of calcitriol to reg-
The complementary DNA (cDNA) for canine and ulate expression of the insulin receptor has been
feline PTHrP has been cloned and sequenced. 492,555 described, 345 as has a role in muscle. 140 Of particular
The sequence of canine PTHrP cDNA and gene indicated interest in uremic patients is the calcitriol increase of ery-
that the dog PTHrP gene is more closely related to the throid proliferation via burst-forming units. 20 These
human PTHrP gene than are the PTHrP genes in rats, pleiotropic effects of calcitriol can be related to important
mice, and chickens. 226 The deduced amino acid sequence clinical applications in patients with renal or other meta-
of the N-terminal region (amino acids 1 to 36) is identical bolic disease. 252 They may explain the clinical
in five mammalian species (dog, cat, human, rat, and improvements noticed in dog and cat uremic patients
mouse), and there is a high degree of homology of the treated preventively with low doses of calcitriol 401 that
midregion of PTHrP in these species. 350,492,551,555,633 were accomplished when calcitriol was used before any
The high degree of interspecies homology indicates the PTH elevation had occurred.
importance of the N terminus and midregion in the func-
tion of PTHrP. VITAMIN D METABOLISM
There is less homology of the C-terminal region of
canine PTHrP with that from other species. The function The cholecalciferol (parent vitamin D 3 of animal origin)
oftheC-terminalregionisunknown.PTHrP(107to111) metabolites 25-hydroxyvitamin D 3 (calcidiol), 1,25-
and PTHrP (107 to 139) may inhibit osteoclastic bone dihydroxyvitamin D 3 (calcitriol), and 24,25-dihydroxy-
resorption. 182,548 Increased urine concentrations of C- vitamin D 3 are the most important of at least 30
terminal PTHrP have been demonstrated in humans and metabolites. In domestic mammals, the same three
275,288
mice with cancer-associated hypercalcemia and in metabolites derived from vitamin D 2 (ergocalciferol of
patients with renal failure. 89 Increased C-terminal PTH plant origin) are equally bioactive; thus, generic use of
is also seen in the sera of patients with renal failure and the terms 1,25-dihydroxyvitamin D and calcitriol is
indicatesthatthekidneysareanimportantsiteofexcretion assumed to include metabolites of vitamin D 3 or D 2
of C-terminal PTHrP. C-terminal PTHrP may have a lon- derived from animal or plant origin, respectively. The
ger serum half-life than N-terminal or midregion PTHrP. 25-hydroxyvitamin D that is produced in liver is the
major circulating form of vitamin D 209 and serves as a
PARATHYROID HORMONE-RELATED pool for further activation by 1a-hydroxylation or catab-
PROTEIN IN THE FETUS olism by 24-hydroxylation. 243,421 Only 25-hydroxylation

Fetuses maintain higher concentrations of serum iCa than and 1a-hydroxylation are important in the function of
their dams. Fetal parathyroid glands produce low levels of vitamin D. 139
PTH, 105 and PTHrP functions to maintain iCa balance in
the fetus. 342,343 PTHrP is secreted by fetal parathyroid Synthesis
chief cells, and PTHrP is produced by the placenta, which In humans, the requirement for vitamin D can be met by
is necessary for iCa uptake by the fetus. 628 The midregion consumption of vitamin D 2 or D 3 or by synthesis of vita-
of PTHrP is the most active portion that stimulates iCa min D 3 (cholecalciferol) in the skin. Cholecalciferol is
and iMg transport by the placenta. The placenta expresses synthesized in the skin from 7-dehydrocholesterol after
the iCa-sensing receptor, which may contribute to the exposure to ultraviolet light. 7-Dehydrocholesterol