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Phosphate - The Effects Of Phosphate Burden And Organ Dysfunction

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Phosphorus is used by the body as phosphate (PO4). One of the most common minerals in nature and one of the most present in the human body, phosphorus makes up around 1% of the body's weight.

Phosphate keeps the integrity of cellular membranes, nucleic acid structure, ATP production, and almost every other molecular process by phosphorylating or dephosphorylating many enzymes and other proteins that are important for cell function and homeostasis.

With so many uses, the body must keep the blood phosphate level at 2.5-4.5 mg/dl.

Through the interaction of the colon, kidney, and bone, the body maintains phosphate homeostasis. Phosphorus flows in and out of bone through the extracellular fluid pool so that the body can get what it needs.

Alkaline phosphatase, an enzyme, releases the phosphate stored in bones through its enzymatic actions.

COPYRIGHT_OAPL: Published on https://www.oapublishinglondon.com/hh/phosphate/ by Alexander McCaslin on 2022-07-22T06:03:18.644Z

Alkaline phosphatase is a protein that is found on the outside of the cell membrane. Its job is to speed up the hydrolysis of organic phosphate esters in the extracellular space so that they can release phosphate into the cell.

Phosphate homeostasis is another job of the kidneys. The main place where phosphate is reabsorbed is in the proximal tubule.

How Is Phosphate Formed?

Phosphate is a type of sedimentary rock that originated on the ocean floor many millions of years ago as a result of the accumulation of various organic compounds. Phosphate was formed as a result of this process.

However, the world's largest deposits of phosphate can be found in Morocco, which is also one of the world's leaders in the phosphate extraction industry. Phosphate reserves can be found throughout Africa, North America, Kazakhstan, the Middle East, and Oceania; however, the world's largest deposits can be found in Morocco.

Phosphorus Cycle Steps

What Is Phosphate Used For?

The processing of phosphate rock results in the production of phosphorus, which is one of the three primary nutrients that are utilized in the manufacture of fertilizers (the other two are nitrogen and potassium).

Phosphate can also be converted into phosphoric acid, an acid that has a wide range of applications, ranging from cosmetics and food to animal feed and electrical components.

Phosphate Burden And Inflammation

Recent research suggests that phosphate overload may cause gingival irritation and dental damage in children. Increased salivary phosphate is linked to greater inflammatory markers and could predict childhood obesity. Hyperphosphatemia causes immunological dysfunction.

When secondary hyperparathyroidism, uremia, or inadequate dialysis were accounted for, high phosphate levels early in dialysis were linked to an increased risk of infection. ESRD patients exhibit decreased cell-mediated immunity and a low CD4+/CD8+ T lymphocyte ratio.

ESRD causes oxidative stress and uremic toxicity, which reduces T lymphocyte counts. Researchers found that there was a negative relationship between the severity of hyperphosphatemia and the number of naive T lymphocyte subsets. This suggests that hyperphosphatemia might lower the number of T cells in ESRD.

Age-related immune system loss makes older people more susceptible to bacterial pneumonia and influenza. Sosa et al. found greater pro-inflammatory cytokine expression and serum phosphate levels in older mice.

Low-phosphate diets reduced cytokine levels. Hyperphosphatemia induces inflammation in vivo as Interleukin-1β (IL-1β) expression correlates with serum phosphate levels. IL-1β is crucial for acute host responses and pathogen resistance, but it worsens chronic illness and acute injury.

As measured by the ratio of 8-hydroxy-2′-deoxyguanine to creatinine (8-OHdG/Cr) in the urine and serum TNF-α. 8-OHdG is a DNA repair metabolite that is quantifiable in the urine.

Macrophages or monocytes emit TNF-α, which causes necrosis or inflammation. Dietary phosphate loading raises TNF-α in a dose-dependent manner; serum TNF-α levels correlate with urinary 8-OHdG/Cr levels (an indicator of oxidative stress). TNF-α and OHdG/Cr levels were reduced by lowering phosphate intake or serum levels.

Phosphate Burden And Aging

Aging is a complex biological process where age-related changes accumulate over time and increase susceptibility to disease and mortality. After 30, it reduces cardiac output by 1% a year due to diminished catecholamine and cardiac glycoside response.

Age-related stiffening of arteries, especially the aorta, increases afterload, or the load against which the heart must contract to evacuate blood. Natural lipid deposits in arteries enhance arteriosclerosis and coronary artery disease risk.

Reduced lung volume and elastic recoil increase residual volume, or air that can't be breathed. Decreasing elastic recoil increases airway collapse, causing ventilation-perfusion imbalances. By age 65, kidney size and glomeruli fall by 30%. Many age-related changes aren't pathogenic, yet they increase the risk.

Hyperphosphatemia is most typically caused by renal failure, as the kidneys eliminate up to 90% of daily phosphate. High phosphate levels are caused by overconsumption, vitamin D poisoning, and hereditary disorders.

Hypocalcemia, vascular calcifications, and arteriosclerosis are hyperphosphatemia symptoms. High levels of phosphate can lead to coma, seizures, delirium, neuromuscular excitability, muscle cramps, tetany, and problems with thinking.

Due to calcium-phosphate precipitation, it causes cataracts and conjunctivitis. Renal failure reduces calcitriol production and causes secondary hyperparathyroidism, which increases osteoclastic bone resorption and calcium and phosphate release into the circulation, leading to more fractures.

Hyperphosphatemia reduces endothelial nitric oxide (NO) generation due to oxidative stress, causing cell viability and death. High phosphate causes endothelial cell senescence by cell cycle arrest, not apoptosis.

Phosphate: a story of plants, science and our survival

Phosphate Burden And Cardiovascular Pathology

Hyperphosphatemia inhibits endothelial cell function through endothelin-1 and NO imbalances, leading to endothelial dysfunction, a key step in the pathophysiology of atherosclerosis that can impair renal and cardiac functions.

High phosphate levels lead to endothelial dysfunction by reducing NO generation via bradykinin and increasing ROS.

Hyperphosphatemia reduces intracellular calcium, increases protein kinase C-B2, and reduces cell survival. Hyperphosphatemia accelerates vascular aging by collagenizing the tunica media in artery walls, where phosphate and calcium crystals accumulate.

FGF23 reduces blood phosphate. Bone secretes FGF23 when phosphate levels are high, which increases phosphate excretion by the kidney. FGF23 inhibits cytochrome P27B1 and stimulates cytochrome P24, reducing 1,25(OH)2D3.

Vitamin D promotes calcium and phosphate absorption in the intestines and mobilizes bone tissue to boost phosphate and calcium blood levels. Mutated FGF23 causes severe hyperphosphatemia.

FGF23 gene deletion in mice causes hyperphosphatemia, proving its role in lowering serum phosphate. Non-functioning FGF23 shortened the longevity of mice. This shorter lifetime was partly attributable to tissue and organ atrophy and vascular calcification.

Hyperphosphatemic mice had lower adipose and skeletal muscle mass, indicating hastened aging. FGF23-deficient mice were sterile, hypoglycemic, and had high cholesterol.

Phosphate Burden And Muscular Pathology

High phosphorus increases skeletal muscle atrophy through unknown processes. Increased phosphate levels cause muscle atrophy due to reduced microtubule size, increased ROS formation, decreased protein synthesis, and rapid protein breakdown.

This is especially critical for older people, whose musculoskeletal systems tend to deteriorate. Sarcopenia is an age-related loss of muscular mass and strength. Hyperphosphatemia causes cellular senescence in mouse myoblasts, leading to sarcopenia.

Cellular senescence involves cell cycle arrest. Myoblasts sened due to hyperphosphatemia-induced mTOR activation and reduced autophagy via Integrin-linked kinase (ILK) activation. Suppressing ILK expression boosted autophagy and protected myoblasts from hyperphosphatemia-induced senescence. Sarcopenia is caused by myoblast loss.

Hyperphosphatemia induces senescence in cultured myoblasts through ILK overexpression via gene transfer utilizing adenoviral expression vectors carrying the ILK gene and lowers cell replication capacity since older animals lose muscular strength, which coincides with hyperphosphatemia and elevated ILK and p53.

Overexpression of ILK increases the cell cycle inhibitor p53. CKD can also accelerate muscle loss. Muscle atrophy is a serious concern in CKD patients, and muscle preservation is key to treatment and prognosis.

A high phosphate burden may decrease myogenic differentiation in vitro and accelerate skeletal muscle atrophy in CKD. This is done by increasing ROS production and p62 expression, which both boost Nrf2 transcriptional activity.

Kelch-like ECH-associated protein 1 blocks Nrf2's DNA binding (Keap1). Oxidative stress inactivates Keap1, allowing Nrf2 to impact drug metabolism, oxidant signaling, and antioxidant defense.

P62 induces body forms and targets ubiquitinated proteins for digestion. Animal studies suggest that hyperphosphatemia enhances inflammation to aggravate anemia and skeletal muscle wasting.

Phosphate load induces hepatic levels of IL-6 and IL-1β to enhance the expression of hepcidin, a putative relationship between hyperphosphatemia, anemia, and skeletal muscle dysfunction. Hepcidin blocks intestinal iron absorption and macrophage iron recycling at high levels.

Phosphate Burden And Renal Pathology

CKD causes hyperphosphatemia, which increases the risk of heart disease. Kidneys excrete phosphate to maintain appropriate levels. CKD causes more non-functioning nephrons and more body phosphate.

CKD prevents most people from aging successfully. Successful aging means aging without CVD, cancer, COPD, and personal/cognitive damage. Sarnak et al. hypothesized three reasons why CKD promotes ineffective aging.

First, vascular disease or hypertension may cause renal dysfunction. Second, kidney function may increase anemia, insulin resistance, and inflammation, all aging risk factors. Third, renal dysfunction may be connected to insufficient glomerular filtration rates (GFR).

Early CKD can cut life expectancy by 5 years. CKD affects mineral metabolism, bone composition, and GFR. CKD-MBD results. Serum calcium and phosphate rise with decreased GFR.

Mineral homeostasis disruption raises PTH, FGF23, and calcitriol. This increases bone turnover and extra-skeletal calcifications. Hyperphosphatemia, vascular calcification, and high FGF23 concentrations are components of CKD-MBD, which worsens cardiovascular disease and accounts for 60% of the fatalities among CKD dialysis patients.

A big grey phosphorus rock on a white background
A big grey phosphorus rock on a white background

People Also Ask

What Do Phosphates Do In The Body?

The element phosphorus can be found in the chemical compound known as phosphate. Phosphates are necessary for the production of energy, as well as for the proper functioning of muscles and nerves, and for the formation of bones.

Is Phosphate Harmful To The Body?

Phosphate at high concentrations can be poisonous. A high concentration of the mineral can lead to diarrhea, in addition to the stiffening of organs and other soft tissues. Phosphorus can interfere with the body's ability to make effective use of other minerals, including iron, calcium, magnesium, and zinc, if it is present in high concentrations.

What Happens If Your Phosphate Levels Are Too High?

Phosphate is essential for the health of your bones and teeth, as well as the production of energy and the formation of cell membranes in your body. Phosphate is essential for bone and muscle health, but too much of it can increase your risk of heart attack and stroke in addition to causing bone and muscle problems. Phosphate levels that are too high are frequently an indication that the kidneys are damaged.

What Foods Contain Phosphate?

Protein foods, such as milk and milk products, as well as meat and substitutes, such as beans, lentils, and nuts, are good sources of phosphorus since these foods contain high concentrations of the mineral. Phosphorus can be obtained through cereals, particularly whole grains. Phosphorus is found in food sources, including vegetables and fruit, although in much lower concentrations.

Conclusion

An essential nutrient with a number of functions in the human body is phosphate. It is crucial to maintain its concentration within healthy homeostatic ranges to reduce the likelihood of developing the various systemic diseases that were previously addressed.

Hyperphosphatemia affects many parts of aging faster, such as sarcopenia, decreased immune function, skin atrophy, the start of arteriosclerosis, the development of cancer, and the progression of different neurological diseases.

By using phosphate scavengers to reduce the phosphate burden, potential therapies to delay phosphate-associated aging-like characteristics might be possible. Another option is to lower dietary phosphate consumption, which can be done by avoiding processed meals with artificial phosphate additions.

Since phosphate is frequently found in additives and preservatives, the FDA does not require the food industry to publish phosphate levels on labels, which makes it much harder to regulate how much is consumed.

In conclusion, it's becoming more and more clear that hyperphosphatemia is a major cause of aging that happens faster than normal. This shows how much more interventional research is needed, which could lead to big advances in medicine.

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About The Authors

Alexander McCaslin

Alexander McCaslin

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