Kidney calcium reabsorption

Increasing calcium reabsorption from the proximal tubules in the kidney... 

Calcium is freely filtered along with other components of the plasma through the nephrons of the kidney. Most of this calcium is reabsorbed into the blood from the proximal tubule of the nephron. However, because the kidneys produce about 1801 of filtrate per day, the amount of calcium filtered is substantial. Therefore, the physiological regulation of even a small percentage of calcium reabsorption may have a significant effect on the amount of calcium in the blood. Parathyroid hormone acts on the Loop of Henle to increase the reabsorption of calcium from this segment of the tubule and... 

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. 

DHCC also facilitates calcium reabsorption in the kidney and mobilizes calcium from bone when PTH is also present. All these actions help bring blood calcium levels back within the normal range. 

The polypeptide parathormone is released from the parathyroid glands when plasma Ca + level falls. It stimulates osteoclasts to increase bone resorption in the kidneys, it promotes calcium reabsorption, while phosphate excretion is enhanced. As blood phosphate concentration diminishes, the tendency of calcium to precipitate as bone mineral decreases. By stimulating the formation of vit D hormone, parathormone has an indirect effect on the enteral uptake of Ca + and phosphate. In parathormone deficiency, vitamin D can be used as a substitute that unlike parathormone, is effective orally. 

PTH is secreted from the parathyroid glands in response to a low plasma concentration of ionized (free) calcium. PTH immediately causes the transfer of labile calcium stores from bone into the bloodstream. PTH increases rates of dietary calcium absorption by the intestine indirectly via the vitamin D3 system activation of enterocyte activity. Within the kidney, PTH directly stimulates calcium reabsorption and a phosphate diuresis. 

In the kidney, PTH stimulates the conversion of 25-(0H)D3 into 1,25-(0H)2D3. Intrarenal l,25-(OH)2D3 causes an amplification of the PTH-induced calcium reabsorption and phosphate diuresis. l,25-(OH)2D3 enhances PTH action in bone also. Once again, PTH does not directly affect intestinal calcium absorption, but it does so indirectly through induction of l,25-(OH)2D3 synthesis and enhanced enterocyte absorption. 

Vitamin Dj, through its active metabolite, 1,25-(0H)2D3, also plays an important role in maintaining calcium homeostasis by enhancing intestinal calcium absorption, PTH-induced mobilization of calcium from bone, and calcium reabsorption in the kidney. 

FUNCTION Maintains the level of calcium in the blood, acting mainly on bone and kidney. In bone, PTH stimulates osteoclast cells to produce bone breakdown with release of calcium and phosphorus (PTH has a similar effect in this regard as vitamin D, but operates by a different mechanism PTH acts through cyclic AMP). In the kidney, PTH increases calcium reabsorption and phosphate excretion (vitamin D, however, increases absorption of both calcium and phosphorus in the kidney). 

Parathyroid hormone (PTH) Peptide Kidney Increased calcium reabsorption. 

In the kidneys, PTH (1) induces 25-hydroxyvitamin D-la-hydroxylase, increasing the production of l,25(OH)2D, which stimulates intestinal absorption of both calcium and phosphate, (2) increases calcium reabsorption in the distal convoluted tubule of the nephron, (3) decreases reabsorption of phosphate by the proximal tubule, and (4) inhibits Na -H antiporter activity, which favors a mild hyperchloremic metabolic acidosis in hyperparathyroid states. 

The common N-terminal explains the ability of PTHrP to interact with the PTH/PTHrP receptor, mimicking the biological actions of PTH in classic target tissues, including bone and kidney. Like PTH, PTHrP causes hypercalcemia and hypophosphatemia t and increases urinary cyclic AMP. However, when compared with patients with primary hyperparathyroidism, patients with PTHrP-induced hypercalcemia have lower concentrations of l,25(OH)2D and more typically have metabolic alkalosis (instead of hyperchloremic metabolic acidosis), reduced distal tubular calcium reabsorption, and reduced and uncoupled bone formation. 

The kidney plays a critical role in calcium homeostasis. PTH acts directly on the kidney to suppress calcium ion excretion in the urine by maximizing tubular calcium reabsorption. It increases phosphate ion excretion in the kidney (phosphaturic effect) to prevent excessive accumulation of this anion released during bone demineralization. 

Calcium homeostasis is modulated by hormones (Fig. 2). Parathyroid hormone (PTH) is the most important calcium regulator. It is a hormone of 84 amino acids, and is secreted from the parathyroid glands in response to a low unbound plasma calcium. PTH causes bone resorption and promotes calcium reabsorption in the renal tubules, preventing loss in the urine. 1,25-dihydroxycholecalciferol (1.23 DHCC) maintains intestinal calcium absorption. This sterol hormone is formed from vitamin D (cholecalciferol). following hydroxylation in the liver (at carbon-25) and kidney (at carbon-1). However.hydroxylation in the kidney is PTH dependent.andsoeven (he absorption of calcium from the gut relies (albeit indirectly) on PTH. 

Dechaux M, Froissart M, May A, Demontis R, Fournier A, Paillard M and Houillier P (2001) Paracellin-1 is critical for magnesium and calcium reabsorption in the human thick ascending limb ofHenle. Kidney Int 59 2206-2215. 

Liesivuori and Savolainen (1991) studied the biochemical mechanisms of toxicity of methanol and formic acid. Formic acid is an inhibitor of the enzyme mitochondrial cytochrome oxidase causing histotoxic hypoxia. It is, however, a weaker inhibitor than cyanide and hydrosulfide anions. The effects of its acidosis are dilation of cerebral vessels, facilitation of the entry of calcium ions into cells, loss of lysosomal latency, and deranged production of ATP, the latter affecting calcium reabsorption in the kidney tubules. Also, urinary acidification from formic acid and its excretion may cause continuous recycling of the acid by the tubular cell Cl-/formate exchanger. Such sequence of events probably causes an accumulation of formate in urine. Other than methanol, methyl ethers, esters, and amides also metabolize forming formic acid. 

As blood calcium levels fall, PTH is released from the parathyroid gland and acts directly upon the kidney and bone as well as indirectly on the intestines. The renal actions of PTH, mostly mediated by cAHP, are summarized in Table I. These direct renal PTH actions, therefore, elevate blood calcium levels by enhancing calcium reabsorption and by lowering blood phosphate concentrations and pH. The latter two actions of PTH allow calcium levels to rise to a greater extent without precipitating calcium phosphate. 

Hypercalcemia of malignancy is a common occurrence in solid tumors of the lung and breast as well as multiple myeloma and adult T-cell lymphoma/leukemia (26). The hypercalcemia associated with breast cancer is usually seen in late stages of the disease in patients with extensive bone metastases. In squamous cell carcinoma of the lung or kidney, however, hypercalcemia is not correlated with disease stage and is not necessarily associated with bone metastases. The hypercalcemia results from increased bone resorption, decreased bone formation and increased renal tubular calcium reabsorption. These findings suggest that some tumors may secrete humoral factors with PTH-like actions. 

While strong evidence exists implicating cadmium as a major causative factor in itai-itai disease, other factors, such dietary deficiencies in minerals and vitamins, may have contributed to the disease (Tsuchiya 1978 Kjellstrom 1986). Serum la,25(OH)2-vitamin D concentrations were depressed in cadmium-exposed cohorts presenting with clinical nephropathy (Nogawa et al. 1987), which suggests that cadmium-induced bone effects may result from disruption of vitamin D and parathyroid hormone metabolism. Because kidney injury results from chronic cadmium exposure, a cadmium-related inhibition of the renal conversion of 25(OH)-vitamin D to la,25(OH)2 Vitamin D may lead to decreased calcium reabsorption, demineralization of bone, and eventually osteomalacia (Friberg et al. 1986). 

An increased risk of osteoporosis correlates with the cadmium burden in different populations, especially for post-menopausal women. Cadmium exposure decreases bone mineral density and thus increases the risk for fractures. These effects on the bones are related to kidney malfunction and poor calcium reabsorption in the nephron, as witnessed by (hyper)calciuria. The consequences of cadmium exposure on the human skeleton were particularly obvious for Japanese living along the Jinzu river basin in the 20th century. Water and rice contaminated by cadmium as a result of zinc-mining activities upstream afflicted the local people with the Itai-Itai disease, a particularly acute and painful form of osteomalacia [44]. 

Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

Parathyroid hormone, a polypeptide of 83 amino acid residues, mol wt 9500, is produced by the parathyroid glands. Release of PTH is activated by a decrease of blood Ca " to below normal levels. PTH increases blood Ca " concentration by increasing resorption of bone, renal reabsorption of calcium, and absorption of calcium from the intestine. A cAMP mechanism is also involved in the action of PTH. Parathyroid hormone induces formation of 1-hydroxylase in the kidney, requited in formation of the active metabolite of vitamin D (see Vitamins, vitamin d). 

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). 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

Vitamin D is a family of closely related molecules that prevent rickets, a childhood disease characterized by inadequate intestinal absorption and kidney reabsorption of calcium and phosphate. These inadequacies eventually lead to the demineralization of bones. The symptoms of rickets include bowlegs,... 

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