Stimulation of Renal Calcium Reabsorption

Almost all of the 240 mmol of ctilcium filtered daily in the kidney is reabsorbed by three mechtmisms (Friedman, 2000)  

In the proximtil tubules, calcium absorption is mainly by a peu-acellular route that is not regulated by hormones. 

In the distal tubule, reabsorption is entirely tremscellulM, and is regulated by pMathyroid hormone and calcitriol (incretising reabsorption) and ctdcitonin (reducing reabsorption). 

Although ctdcitriol is synthesized only in the proximal renal tubule, after the administration of pHJctdcidiol, radioactivity in the kidney accumulates only in the distal and collecting tubules. This is the region in which selective resorption of ctdcium from the urine occurs and, in response to calcitriol, there is induction of C dbindin-D28k. As in the intestinal mucosa, calbindin in the kidney is a cytosolic protein emd is presumably involved in the intracellulM accumulation emd transport of ctdcium. 

In the thick ascending limbs, there are both paracellular and transcellular routes the active transcellular route is regulated by parathyroidhormone (increasing reabsorption) and calcitonin (reducing reabsorption), the paracellular route by cotransport with sodium. 

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This paper summarizes our evidence that the mechanism involves protein stimulation of insulin secretion, followed rapidly by insulin inhibition of renal calcium reabsorption. In humans, urinary calcium was proportional to peak postprandial insulin levels in several experiments, after either protein or sucrose was fed. 

In recent years, we have accumulated considerable evidence that the protein-induced impairment of renal calcium reabsorption, and the subsequent calciuria, are the result of protein-stimulated increases... 

However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less potent stimulators of intestinal calcium and phosphate transport or bone resorption. However, 25(OH)D appears to be more potent than l,25(OH)2D in stimulating renal reabsorption of calcium and phosphate and may be the major metabolite regulating calcium flux and contractility in muscle. Specific receptors for l,25(OH)2D exist in target tissues. However, the role and even the existence of receptors for 25(OH)D and 24,25(OH)2D remain controversial. 

Mechanisms of Renal Water Reabsorption - Much experimental evidence supports the hypothesis, first advanced by Orloff and Handler, that sodium transport and osmotic water flow that characterizes the physiological response to vasopressin.In a recent study. Chase and Aurbach have Identified two distinct adenyl cyclase systems located In renal membrane fractions of rats, one In the cortex and the other In the medulla.While the medullary enzyme was stimulated by vasopressin, cortex adenyl cyclase was more responsive to parathyroid hormone than vasopressin. The localization of parathyroid-sensitive adenyl cyclcise In renal cortex and vasopressin-sensitive adenyl cyclase in renal medulla appears to be consistent with reports that cellular transfer of calcium and phosphate occurs primarily in the proximal portions of the nephron, and sodium transport and water permeability are stimulated by vasopressin mainly In the collecting tubules. Vasopressin-Induced stimulation of adenyl cyclase In the cortex may reflect Its additional action on the distal tubule. 

Dietary calcium has a relatively small impact on urinary calcium (e.g., only 6-8% of an increase in dietary calcium intake will appear in the urine). The major food components that affect urinary calcium are protein, phosphorus, caffeine, and sodium. For each 50-g increment in dietary protein, approximately 1.5 mmol (60 mg) of additional calcium is lost in urine. The higher amounts of phosphorus consumed concurrently with a high-protein diet can blunt, but not eliminate, this phenomenon. Dietary phosphorus (as well as intravenously administered phosphorus) increases PTH synthesis and subsequently stimulates renal calcium reabsorption and reduces the urinary excretion of calcium. Caffeine causes a reduction in renal reabsorption of calcium and a subsequently increased loss of urinary calcium soon after it is consumed. It has been shown repeatedly in animals and humans that dietary sodium, in the form of salt (NaCl), increases urinary calcium excretion. On average, for every 100 mmol (2300 mg) of sodium excreted in urine, there is an approximately 0.6-1 mmol (24-40 mg) loss of calcium in free-living healthy populations of various ages. Because most of the urinary calcium is of bone origin, it is commonly hypothesized that those nutrients or food components that are hypercalciuretic are also detrimental to the skeleton. On the other hand, thiazide medications are hypocalciuric and, as such, may have modest positive effects on bone. 

When calcium absorption is chronically low, because of low intakes, poor bioavailability, or conditions that impair intestinal absorption, there is a decrease in the serum ionized calcium concentration. This in turn stimulates the release of PTH, which returns serum calcium to normal by increasing renal calcium reabsorption, stimulating the renal production of 1,25(0H)2D3, and inducing bone reabsorption. The result of long-term calcium deficiency is accelerated bone loss in older individuals or the inability to fully achieve peak bone mass in younger individuals. 

Hydroxy vitamin D pools ia the blood and is transported on DBF to the kidney, where further hydroxylation takes place at C-1 or C-24 ia response to calcium levels. l-Hydroxylation occurs primarily ia the kidney mitochondria and is cataly2ed by a mixed-function monooxygenase with a specific cytochrome P-450 (52,179,180). 1 a- and 24-Hydroxylation of 25-hydroxycholecalciferol has also been shown to take place ia the placenta of pregnant mammals and ia bone cells, as well as ia the epidermis. Low phosphate levels also stimulate 1,25-dihydtoxycholecalciferol production, which ia turn stimulates intestinal calcium as well as phosphoms absorption. It also mobilizes these minerals from bone and decreases their kidney excretion. Together with PTH, calcitriol also stimulates renal reabsorption of the calcium and phosphoms by the proximal tubules (51,141,181—183). 

We have tested the hypothesis that insulin inhibits the stimulatory effect of parathyroid hormone (PTH) on calcium reabsorption in the distal nephron. PTH is known to enhance calcium transport in renal cells, probably by stimulation of adenylate cyclase and subsequent increases in 3 5 cyclic AMP productoin. Since insulin had been observed to inhibit PTH-stimulated increases in kidney cyclic AMP levels in vitro (24) we investigated whether insulin-mediated hypercalciuria was dependent on the presence of PTH in vivo. 

BY PTH Even modest reductions of serum Ca stimulate PTH secretion. Acutely, the regulation of tubular Ca reabsorption by PTH suffices to maintain plasma Ca homeostasis. With more prolonged hypocalcemia, renal la-hydroxylase is stimulated this enhances the synthesis and release of calcitriol, which directly stimulates intestinal calcium absorption (Figure 61-3). Finally, PTH and the resulting increase in calcitriol also stimulate Ca release from bone. 

The role of 1,25-(OH)20 in the kidney is even less well understood, although its localization in the distal renal tubule cells, specifically in the nuclei, is known. No clear role for l,25-(OH)2D2 in renal tubular reabsorption of phosphorus has been established, and this area remains controversial. There is evidence that 1,25-(OH),D, stimulates renal reabsorption of calcium in the distal tubule but little else is known concerning that mechanism. ... 

Bone is the body s calcium reservoir. PTH stimulates bone resorption leading to the dissolution of hydroxyapatite and release of calcium and phosphate into the blood. This action of PTH appears to be the major mechanism for the rapid elevation of blood calcium levels. PTH also maintains blood calcium levels by promoting calcium reabsorption from the renal tubules. 

Calcium ion activity in blood is strictly regulated by a hormonal feedback mechanism. When the activity tends to decrease, the parathyroids secrete parathyroid hormone (PTH), which stimulates renal tubular reabsorption of Ca , K , and Na and decreases the reabsorption of phosphate. The net effect is a decreased excretion of Ca , Na" ", and K and an increased excretion of phosphate. PTH stimulates the hydroxylase activity in the kidney, and there is a negative feedback system which means that an increased amount of 1,25(OH)2D3 inhibits this hydroxylation procedure. Other hormones such as prolactin, estrogen, and growth hormone also stimulate hydroxylase activity, as does as a low serum phosphate concentration [6]. 

There are many examples in mammalian cells in which the effectuation of hormone action is associated with variations in calcium concentration in the different cellular compartments. Such hormonal actions include stimulation of corticosteroid secretion in the adrenal, the effect of parathyroid hormone on renal tubules, reabsorption and release of calcium from the bone, the effect of melanocyte hormone on melano-phores, the stimulation of smooth muscle contraction by acetylcholine and its retraction by epinephrine, the effect of epinephrine on heart contraction, etc. The role of calcium in the sequence of steps following the hormonal stimulus is often difficult to interpret. 

Vitamin D hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body it is formed in the skin from dehydrocholesterol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, cod liver oil being a rich source. Metaboli-cally active vitamin D hormone results from two successive hydroxylations in the liver at position 25 ( calcifediol) and in the kidney at position 1 ( calci-triol = vit. D hormone). 1-Hydroxylation depends on the level of calcium homeostasis and is stimulated by parathormone and a fall in plasma levels of Ca or phosphate. Vit D hormone promotes enteral absorption and renal reabsorption of Ca and phosphate. As a result of the increased Ca + and phosphate concentration in blood, there is an increased tendency for these ions to be deposited in bone in the form of hydroxyapatite crystals. In vit D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic Liillmann, Color Atlas of Pharmacology... 

It is now well established that l,25-(OH)2D3 is the active hormonal form of vitamin D3 [32], The production of l,25-(OH)2D3 in the kidney is regulated by dietary calcium and phosphate and also by changes in serum calcium and parathyroid hormone, which clearly highlight the hormonal nature of this compound. Functionally, the three classical actions of l,25-(OH)2D3 are to stimulate intestinal calcium and independently phosphate absorption, the mobilization of calcium from bone, and increase renal reabsorption of calcium. The focus of this review will be to explore the most recent concepts of vitamin D in regard to its metabolism and physiology, and with respect to the medicinal applications of vitamin D3 metabolites and analogues. 

Renal failure is associated with an osteomalacia-like syndrome, renal osteodystrophy, as a result of the loss of calcidiol 1-hydroxylase activity. The condition may be complicated by defective reabsorption of calcium and phosphate from the urine. Furthermore, the half-life of parathyroid hormone is increased, because the principal site of its catabolism is the kidney, so there is increased parathyroid hormone-stimulated osteoclastic action without the compensatory action of calcitriol (Mawer etal., 1973). 

Since 1,25-(OH)2D3 production responds slowly to parathyroid hormone a more quickly-reacting system is needed to prevent low calcium tetany. Parathyroid hormone secretion and action is very rapid as is the lifetime of the hormone itself Thus parathyroid hormone can, with endogenous 1,25-(0H)2D3, stimulate the mobilization of calcium from bone and renal reabsorption of calcium but not intestinal absorption Nevertheless, plasma calcium rises but... 

General metabolic significance. Vitamin D stimulates intestinal absorption of calcium and phosphate, renal reabsorption of these ions, deposition and mobilization of minerals in the hard tissue, controlling normal calcium and phosphate blood level by means of these processes. Molecular mechanism of the vitamin D effects most frequently conform to the effect of steroid hormones (induction of protein biosynthesis). 

Calcium homeostasis is maintained by hormonal regulation of the intestina absorption and renal reabsorption. During growth and lactation, body calcium requirements increase and the efficiency of calcium absorption can increase more than 60% compared with the adult steady-state conditions. With age and loss of estrogen stimulation this adaptive ability is blunted. 

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