this is the 5th lecture in the series on the kidney and talks about the kidneys' role in the regulation of calcium and phosphate levels. the kidney is one of three regulatory sites for calcium blood levels, the other two being the intestine and the bone. falling blood calcium levels trigger the release of parathyroid hormone from the parathyroid glands, which has a multifaceted effect that ultimately raises blood calcium levels.
in the kidney, the 60% of calcium that is filtered (meaning not bound to blood proteins) is mainly reabsorbed in the proximal convoluted tubule in a fashion similar to the reabsorption of sodium. PTH regulation plays a role in the reabsorption of calcium in the thick ascending limb and distal convoluted tubule; by upregulating calcium channels and pumps in the tubular epithelium. it also downregulates phosphate transporters, leading to the simultaneous decreasing of phosphate reabsorption. the rationale behind this is that high phosphate levels and calcium levels would lead to mineralization in non-bone tissues.
in the intestines, PTH stimulates calcium absorption from the gut by way of regulating the synthesis of vitamin D into its active form. vitamin D then activates calcium channels and calbindin, which transports calcium across the cells.
in the bones, PTH regulates blood calcium levels by maintaining the balance between calcium being deposited onto new bone surfaces by osteoblasts (deposition) vs. calcium being released into the bloodstream by the breakdown of bone by osteoclasts (resorption). in general, PTH stimulates osteoclast activity by signalling apoptosis in osteoblasts, thereby raising calcium levels. if PTH is pulsed, however, osteoblast apoptosis is inhibited and deposition by osteoblasts can actually be stimulated.
a few pathologies related to calcium regulation: hyperparathyroidism results in the excess secretion of PTH and thus excessively high blood Ca2+ levels, as well as a loss of calcium levels in the bone. hypoparathyroidism is the opposite condition which results in low blood calcium levels. osteomalacia is a demineralization of the bone which results from a deficiency of calcium or vitamin D. osteoporosis is also a demineralization of the bone which results in the loss of bone matrix, not just calcium.
questions
1. what are calcium and phosphate used for in the body?
2. how closely regulated are calcium levels in the body?
3. where are the main sites for homeostatic control of calcium levels?
4. what are the primary hormones that provide homeostatic maintenance of calcium and phosphate levels?
5. what form is calcium found in the body? how much is filtered in the kidney?
6. how does acidosis relate to Ca2+ in the blood? what does it result in?
7. how does alkalosis relate to Ca2+ in the blood? what does it result in?
8. PTH is secreted in response to...
9. describe the reabsorption of Ca2+ in the kidney.
10. describe PTH's control over phosphate reabsorption.
11. why does PTH stimulate reabsorption of Ca2+ and simultaneous excretion of PO4-?
12. describe vitamin D's role in intestinal calcium absorption.
13. describe PTH's role in vitamin D synthesis.
14. describe vitamin D's role in intestinal phosphate absorption.
15. what are the two factors that regulate bone formation and remodeling?
16. describe how stress regulates remodeling of bone.
17. calcium and phosphate are stored in bone in the form of...
18. how is hydroxyapetite formation inhibited in non bone tissues?
19. how do osteoblasts overcome the solubilizing of calcium and phosphate by pyrophosphate in bone?
20. what is calcitonin and where is it released from?
21. how does calcitonin lower blood Ca+ levels?
22. how does PTH stimulate deposition of bone?
23. how does PTH stimulate resorption of bone?
24. how is PTH used to control the balance between deposition/resorption of bone?
25. what effect does hyperparathyroidism have on Ca2+ levels?
26. what effect does hypoparathyroidism have on Ca2+ levels?
27. osteomalacia is...
28. osteoporosis is...
answers
1. muscle contraction, secretion of neurotransmitters, hormones, enzymes, etc.
2. very closely, varying only 1-2% daily or weekly
3. kidney, bone, intestines
4. parathyroid hormone, vitamin D, calcitonin
5. 40% protein bound (and thus not filterable by the kidney), 10% in Ca2+ form, 50% bound to anions. 60% filtered in the kidney.
6. H+ compete with Ca2+ for sites on albumin, which transports the ions in the blood. if the pH is low, then there is less protein bound calcium and thus more free ionized form. this causes decreased neural activity and muscle weakness.
7. if there are less H+ in the blood, then Ca2+ binds to proteins in the blood and reduces the free ionized form. this causes neuromuscular irritability and CNS problems.
8. a fall in blood Ca2+ level.
9. 2/3 of the Ca2+ is reabsorbed in the proximal convoluted tubule, and 1/3 is reabsorbed in the thick ascending loop and distal convoluted tubule. PTH provides fine control over Ca2+ reabsorption in the ascending loop and distal convoluted tubule.
10. PTH inhibits reabsorption of phosphate in the proximal convoluted tubule, where most phosphate reabsorption takes place.
11. because raising both phosphate and calcium levels could create calcium phosphate in soft tissues.
12. vitamin D upregulates of calcium membrane transporters as well as calbindin, which carries calcium across the cell.
13. PTH, secreted in response to falling Ca2+ levels, regulates the synthesis of 1,25 hydroxylated vitamin D- the active form.
14. vitamin D upregulates Na-PO4 cotransporter in intestinal cells.
15. hormones and physical stress.
16. stress creates a piezoelectric effect that initiates osteoblast (bone building) and osteoclast (bone destroying) activity on opposing surfaces which remodels bone.
17. hydroxyapetite: Ca10(PO4)6OH2
18. it remains in soluble form by pyrophosphate.
19. osteoblasts contain alkaline phosphatases that cleave pyrophosphates, freeing calcium and phosphate to form bone.
20. a hormone that is released in response to rising Ca2+ levels that counters the effects of PTH. released from parafollicular cells of the thyroid.
21. by inhibiting osteoclast activity; free Ca2+ is then used to deposit bone by osteoblasts.
22. PTH stimulates osteoclast activity, which can induce release of growth factors from bone matrix which can in turn stimulate osteoblast deposition of bone.
23. PTH stimulates osteoblast to initiate RANK/RANKL paracrines which activates osteoclasts and thus stimulates bone resorption.
24. if PTH is secreted intermittently, osteoblast apoptosis is inhibited and deposition occurs. if PTH is secreted continuously, osteoblasts continue to undergo apoptosis and osteoclast activity resorbs bone.
25. excess secretion of PTH causes blood Ca2+ levels to rise and bone density to fall.
26. reduction in osteoclastic activity reduces resorption of calcium and lowers blood calcium levels.
27. demineralization of bone resulting from deficiency in calcium or vitamin D.
28. loss of bone matrix
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