Water plays an important role in life processes, not only as a necessary component of all cells and tissues of the organism, but also as a medium in which all chemical transformations connected with the life of the organism occur. Salt metabolism is intimately connected with the water metabolism. Most of the mineral compounds in the organism are in water solutions. Salts, like water, are not sources of energy to the organism, but they are a part of all cells and tissues and are a necessary part of it.
The water content in the human organism is about two thirds of organism weight, decreased slightly with age. Higher water content is in newborns. Some of the water, part of the organism tissues, is in a bound form in them. For example, such compact tissues and organs, like muscles, skin, kidneys, heart, include 70-80% of water.
Water has a number of specific chemical and physical properties. Clean water is a neutral liquid, which dissolve well various inorganic and organic substances. Due to the large dielectric coefficient water facilitates the electrolytic dissociation of dissolved electrolytes. A small viscosity of water, which depends on the speed of movement of fluids in the blood and lymphatic vessels, tissue crevices, etc., is also one of its important properties.
All chemical reactions and physico-chemical processes in the human organism occur in the aqueous environment. This is hydrolysis reactions, where the water is directly involved in the reaction, many oxidation reactions, hydration, colloids swelling and other.
Water plays an important mechanical role in facilitating the sliding of the friction surfaces (joints, ligaments, muscles, etc.). Evaporation of the water through the skin is an ability by which a person maintains a constant organism temperature during the formation of strong heat in the organism or at high ambient temperature.
The main parameters of the liquid medium of the organism are the osmotic pressure, pH and volume. Osmotic pressure and pH of the extracellular fluid and blood plasma are the same. The pH inside the cells of different types may be different depending on the characteristics of metabolic mechanisms of active transport, selective permeability of membranes. Maintaining constant intracellular environment is provided by the constancy of the osmotic pressure, pH and volume of extracellular fluid and blood plasma, and they, in turn by the action of the kidneys and hormones that regulate their function.
Man can not stand any significant dehydration and die from lack of water much faster than from lack of food. Adult daily requirement of water is about 40 grams of water per 1 kg body weight. Water requirement is met by the intake of various liquids (drinking water, beverages, soups) – 1-1.5 liters; water of foods – about 1-1.5 liters; water that forms in tissues of the oxidation of various substrates of tissue respiration – about 400 ml.
The amount of water formed during the oxidation of 100 g of various nutrients is expressed by the following figures: the lipid – 107 ml, carbohydrate – 55 ml, protein – 41 ml; 12 ml of water is formed from 100 calories during the usual mixed diet.
The water coming from outside should fully compensate for the constant loss of water through the kidneys (urine), skin (sweat), lungs (breathing), intestine (feces). This loss of water is linked to the implementation of a number of important physiological functions. The main part of the end products of nitrogen metabolism in humans is excreted through the kidneys into the urine. In humans, depending on body weight and sex, in this way about 1.2-1.5 liters of water are excreated during the day. By drinking plenty of fluids, the diuresis is increased, and conversely, urine amount is decreased at the restriction of drinking. Condensation of the urine is possible only to a certain limit. Excessive restriction of water intake inevitably leads to violation of excretion of metabolism products, in particular nitrogen waste products. A large part of mineral salts (sodium chloride, phosphates, etc.) is excreted in soluble form in urine from an organism. The retention in the body of these salts, as well as various nitrogenous constituents of urine quickly would lead to incompatible with life changes of plasma blood osmotic pressure, interstitial fluid and intracellular contents.
Maintaining the concentration of water in various tissues of the human body at a certain level is done by the special mechanisms of the regulation, in particular a sense of thirst. Thirst is the result of reflex excitation of certain parts of the cerebral cortex at the first sign of changes in osmotic pressure of blood plasma. Absorption of water entering the body through the mouth, begins in the stomach, but most of it goes into the blood capillaries and and partly lymphatic vessels in the gut. The osmotic pressure of blood is usually higher than the osmotic pressure of the chyme; the absorption of water does not require any energy consumption. Absorbed water is partly retained in the liver; part of it enters the systemic circulation. However, no significant liquefaction of the blood (hydremia) was observed even after absorption of large quantities of water (at once 1.5 liters). This is explained by the fact that the large mass of absorbed water is immediately transferred from the blood into the intercellular fluid, as well as the abdominal cavity. The skin and liver play a particularly important role as the organs that hold the excess of absorbed water.
Water metabolism is not isolated and independent from the metabolism of other substances. This relationship is most significant with mineral metabolism. Sodium salts cause water retention in the tissues. Potassium and calcium salts help to remove water from the body. The water balance is also depends on the content of proteins, lipids and carbohydrates in food. The diet rich in carbohydrates provides a significant increase in body weight; but especially children become a kind of "loose" due to the retention of large amounts of water in their bodies. The lipopexia in the body, by contrast, is not accompanied by water retention, but rather leads to a negative water balance.
If more water is introduced into the body than it can be excreted through the kidneys; sweating starts, accompanied by headache, nausea and general weakness.
Excretion of water from the body is controlled by several mechanisms; the most important of which is a mechanism for the regulation of uropoiesis. It will be reviewed in the section "Biochemistry of the kidneys".
6.2. Salt metabolism
Metabolism of water, as already noted, is intimately connected with the salt metabolism. Salt is not only part of the structural elements of cells and tissues, but it also participates in a variety of metabolic processes between the cells and intercellular fluid. They activate a number of enzymatic systems, play a vital role as necessary components of all biological fluids and enable normal functioning of the body. In the largest amount, mineral compounds (Ca, Mg, F, and P) are part of the bone tissue and teeth. Calcium and magnesium in the bones are in the form of phosphates, and some carbonates and fluoride. Calcium and magnesium are in the ionized state of the cells of other tissues, blood plasma and all body fluids. Parts of the cations (especially Ca2+ and Mg2+) are presented in the body in the associated with proteins form. This part of the cations is not osmotically active and is not involved in the activation of enzyme systems.
Calcium (Ca) is macroelement plays an important role in the functioning of muscle tissue, the myocardium, nervous system and skin. In ionized form (Ca2+) it circulates in the blood and interstitial fluid; it takes part in the regulation of neuromuscular conduction, vascular tone, hormone production, capillary permeability, reproductive function, blood clotting; it prevents the deposit of toxins, heavy metals and radioactive elements in the body. The normal serum calcium content is 92.2-110.2 mg/kg.
Magnesium (Mg) is the main intracellular element. It activates enzymes that regulate carbohydrate metabolism, stimulates the production of proteins, regulates the storage and release of energy in ATP, reduces the stimulation of nerve cells, relaxes heart muscle. Normally, the serum content of P is 17-29.2 mg/kg.
Phosphorus (P) is an important nutrient element found in the body not only in the form of inorganic phosphate salts, but it is also a part of nucleoproteins and nucleotides, phosphoproteins, phosphatides, carbohydrates phosphoric esters, etc. Phosphorus is essential for the normal functioning of the nervous system (ensures the conduction of a nerve impulse), bones and muscles (it provides muscle contraction). It is involved in cell growth, cell division, storage and use of genetic information; it reduces vascular permeability and blood cholesterol levels.
Sodium and potassium are found in the body mostly in the form of ions in all tissues. Sodium is found in extracellular fluids (blood plasma, lymph, digestive juices, and exudates), in the form of salts – chloride, phosphate and bicarbonate. Potassium, on the contrary, usually dominates the contents of cells.
Sodium (Na) is a macroelement, electrolyte; it plays a very important role in water and salt metabolism, regulation of neuromuscular activity and renal function. The serum content of Na is normally 2900-3588 mg/kg.
Potassium (K) is the most important element, electrolyte and activator of function of several enzymes. K regulates the intracellular metabolism, the metabolism of water and salts, and supports the osmotic pressure and acid-base state of the body; promotes normal functioning of the muscle,is involved in conducting nerve impulses to muscles; promotes excretion of water and sodium; it also activates several enzymes and is involved in important metabolic processes (energy production, synthesis of glycogen, proteins, glycoproteins); moreover it is involved in the regulation of the process of insulin secretion by cells of the pancreas; supports smooth muscle cell sensitivity to the vasoconstrictor action of angiotensin. he serum content of K is normally 135.7-207.117 mg/kg.
Sulfur (S) is a part of almost all the proteins of the body. There is especially a lot of sulfur in proteins of supporting tissues, such as keratin in hair that differs by high content of amino acid cystine. Sulfur is found in the body in the tripeptide glutathione, vitamins, hormones (oxytocin), etc.
Chlorine (C1) is located in the body mostly in the form of an anion of Na, K, Ca and Mg salts. Anions of chlorine are the most important osmotically active ions of blood plasma, lymph, cellular content, cerebrospinal fluid, etc.
Apart from the above salts other elements are also always found in small amounts in the human body.
Cobalt (Co) is required for the body to participate in the process of hematopoiesis, activation of a number of vital enzymes, the functioning of the nervous system, the processes of tissue regeneration, production of thyroid hormones, maturation and development of cells and factors of the immune system, and brain antistress protection. Cobalt is a part of a molecule of vitamin B12. The normal serum content of Co is within 0.07-0.12 mg/kg.
Silicon (Si) is a micro element, the maximum content of it is observed in the skin and in solid tissues – enamel, hair, nails and bones. Silicon plays an important role as a structural component of connective tissue. Normally, the serum content of Si is in the range from 0-3.5 mg/kg.
Manganese (Mn) is vital micro element; it is involved in the functioning of more than 30 enzymes. Manganese is responsible for many processes in the body: synthesis and metabolism of neurotransmitters in the central nervous system; formation of bone and connective tissues, the immune response; it regulates the activity of antioxidant enzymes, insulin and lipid metabolism, the metabolism of thyroid hormones, estrogens. Manganese is necessary for the regulation of metabolism of vitamins C, E, B group, as well as choline. Manganese is a part of the active site of many enzymes; it plays an important role in protecting the body from the harmful effects of peroxide radicals. Normally, the serum content of Mn is 0.01-0.02 mg/kg.
Iron (Fe) is micro element which is closely associated with copper (Cu) and zinc (Zn). Iron is a part of more than 70 proteins and enzymes, hemoglobin, cytochromes, redox enzymes. Iron is essential for the normal functioning of the immune system, bone formation, nervous system, for the gastrointestinal tract, endocrine glands. The main functions of Fe in the body are: electron transport (cytochromes, iron-sulphur proteins); transport and deposition of oxygen (myoglobin and hemoglobin); participation in the formation of active sites of redox enzymes (oxidases, hydroxylases, SOD); activation of lipid peroxidation, pre-prepared by copper ions; transport and deposition of iron (transferrin, ferritin, hemosiderin, lactoferrin); participation in DNA synthesis and cell division; participation in the synthesis of prostaglandins, thromboxanes, leukotrienes and collagen; participation in the metabolism of hormones of the adrenal medulla; participation in the metabolism of aldehydes, xanthine; participation in the catabolism of aromatic amino acids, peroxides. Normally, the serum content of Fe is 0.6-1.8 mg/kg.
Copper (Cu) is a micro element that plays an important role in the regulation of redox processes, and hematopoiesis, the formation of connective tissue. It is involved in the synthesis of hemoglobin and red blood cell production; it is vital for normal bone development, the integrity of the cardiovascular system (hardening of blood vessels and heart muscle). Copper forms elastin; copper is necessary for normal functioning of the immune system; it plays an important role in the development of myelin. Copper is extremely important for iron absorption, controls cholesterol, glucose and uric acid levels. Copper is closely related to zinc and iron. Normally, the serum content of Cu – 0.7-1.4 mg/kg.
Zinc (Zn) is essential micro element that is needed for fission and cell growth, protein and nucleic acid synthesis, regeneration and detoxification processes and immune protection. Most of the zinc in the adult's body is found in muscles, bones and skin. Zinc provides a function of the nervous system (memory, mental capacity, intellectual capacity, taste, smell, vision), the immune system (T-cell immunity, local immunity of the skin and mucous membranes) and reproductive organs (synthesis of sex hormones). Zinc controls the contractility of muscles, needed for protein synthesis (liver), digestive enzymes and insulin (pancreas), detoxification (alcohol, radioactive elements, toxic metals and various chemical agents). Particularly children are in need of zinc, because it regulates the growth of human and influence on his mental and physical development; it has a direct impact on the formation of collagen tissue and skeleton; it plays an important role in the formation of hormones. Zinc is closely associated with copper and iron. Normally, the serum content of Zn is 0.02-1.2 mg/kg.
Selenium (Se) is vital ultra-micro element: it provides antioxidant and disintoxication protection of the body; trophic functions in the central and peripheral nervous system; it involved in maintaining of the nutrition of the skin, cornea and lens, hair and nails. Selenium works synergistically with vitamin E, protects sperm from pollutants and ensures their mobility. Normally, the serum content of Se is 0.14-0.22 mg/kg.
Iodine(I), aluminum (A1), cadmium (Cd), arsenic (As), nickel (Ni), lead (Pb), titanium (Ti), chromium (Cr), barium (Ba), lithium (Li) are also important elements for the functioning of the human body.
Despite the fact that the daily need of the human body in the macro-and micronutrients is often expressed in small parts of a milligram, a number of diseases of metabolic disorders can appear with complete elimination of them from food.
For example, in iron deficiency such pathological conditions are developed as acute and chronic blood loss, hypochromic anemia, and myoglobin deficient cardiomyopathy and atonia of skeletal muscles, inflammation and atrophic changes of the mucous membranes of mouth, nose; esophagopathy, chronic gastroduodenitis, and immunodeficiency states.
With the deficit of potassium such diseases occur as degeneration and diffuse cardionecrosis with dilatation of the cavities of the heart, arrhythmias, nephrosis with sclerosis of the renal tubules, muscular dystrophy and generalized weakness, hallucinations.
The most characteristic manifestations of cobalt deficiency are anemia, abnormal menstrual cycle in women, degenerative changes in the spinal cord, hypo-pigmentation of the skin.
With the deficit of silicon, the non-specific body resistance to various deseases including cancer becomes lower. In children, low levels of silicon can be evidence of degenerative changes, increased fragility and lack of elasticity of blood vessels.
Magnesium deficiency is a common phenomenon for people exposed to chronic stress, common in chronic fatigue syndrome, diabetes mellitus.
Lack of manganese in the body leads to disruption of glucose metabolism in insulin-dependent type of diabetes, hypocholesterolemia, delayed growth of hair and nails, increased convulsive readiness, allergoses, dermatitis, disturbance of cartilage formation, osteoporosis. Manganese deficiency also states in various forms of anemia, reproductive dysfunction, stunted growth, reduced body weight.
Copper deficiency negatively affects the absorption of iron, hemapoiesis, the processes of myelination in the nervous tissue, strengthens propensity for bronchial asthma, allergodermatosis, cardiomyopathy, and to vitiligo; it affects the condition of the connective tissue.
People with a deficiency of zinc are usually often suffered from catarrhal and infectious diseases for long time. Zinc-deficient states are characterized by reduced appetite, anemia, allergies, hyperactivity, dermatitis, underweight, decreased visual acuity, hair loss, and delayed puberty in boys, the loss of the ability of sperm to ovum fertilization in men.
Selenium deficiency gives decreased immunity, increased propensity to inflammatory diseases, decreased liver function, cardiomyopathy, diseases of the skin, hair and nails; atherosclerosis, cataracts, reproductive failure, growth retardation, pulmonary pathology, the rapid aging of the body. Selenium deficiency accelerates the development of atherosclerosis, coronary heart disease, the risk of myocardial infarction. It is proved that there is relationship between selenium deficiency and the frequency of sudden infant death syndrom. The likelihood of male infertility is also increased with selenium deficiency. There is also a relationship between cancer of stomach, prostate, colon and breast cancer and lack of Se.
Minerals and salts are involved in maintaining of osmotic pressure in body fluids on a certain level; they play an important role in the formation of buffer systems of tissue and blood.
7. RENAL BIOCHEMISTRY.
THE ROLE OF THE KIDNEYS IN THE REGULATION OF WATER AND SALT METABOLISM
Kidneyis a paired organ; nephron is the basic structural unit of kidney. About 1000-1300 ml of blood is filtered in the kidneys per 1 minute. Due to the good blood supply, the kidneys are in constant interaction with other organs and tissues and can affect the state of the internal environment of the whole organism. There are the following renal functions: excretory, metabolic and homeostatic.
Excretory function is aimed at removing the end products of catabolism from the body. For example, the products of nitrogen metabolism: urea, uric acid, creatine, and the products of neutralization of toxic substances. Kidneys excrete excess substances sucked into the intestine or formed in the catabolic processes: water, organic acids, vitamins, hormones, etc., as well as xenobiotics – foreign substances (drugs, nicotine, etc.).
Performing homeostatic function, the kidneys regulate water homeostasis, salt homeostasis, acid and base balance.
Metabolic function of the kidneys involves their participation in carbohydrate, protein and lipid metabolism, synthesis of some biologically active substances, rennin, the active form of vitamin D3, erythropoietin, prostaglandins, and kinins. These substances influence the regulation of blood pressure, blood clotting, calcium and phosphorus metabolism, the maturation of red blood cells and other processes.
7.1. Excretory function of the kidneys
The kidneys form urine from the components of blood plasma and can effectively regulate its composition. The uropoiesis process consists of three stages.
1. Ultrafiltration. Primary urine is formed during ultrafiltration. Blood, flowing through vessels of kidneys, is filtered in the glomerulus cavity through the pores of the connective tissue capsule – a special filter, which consists of three layers. The first layer is the endothelium of blood capillaries, which has large pores. All components of blood pass through these large pores, except blood cells and high molecular weight proteins. The second layer is the basal membrane, which is constructed of collagen fibers (fibrils) that form a molecular "sieve". Pore diameter is 4 nm. The basal membrane does not mess proteins with a molecular weight higher than 50 kDa. The third layer is epithelial cells of the capsule; their membranes are negatively charged, so it prevents the negatively charged albumin of blood plasma to penetrate into the primary urine. The form of three-layer pores is complicated; it does not match the form of the protein molecules of blood plasma. This mismatch prevents the penetration of the normal protein molecules into the primary urine. If the structure, shape, charge of the protein molecule is changed from a normal protein molecule, this abnormal protein can pass through the filter and into the urine. This is one of the mechanisms of blood plasma purification of defective proteins and its restoration of normal structure.
Ultrafiltrate (primary urine) is normally almost free of proteins and peptides. But on the other hand, the composition of low molecular weight non-protein components, and the content of various ions in the primary urine is the same as in blood plasma. Therefore, the primary urine is sometimes called "protein-free filtrate of blood plasma". Amount of the produced ultrafiltrate depends on the driving force for ultrafiltration – hydrostatic pressure of the blood vessels in the glomerulus (normal is about 70 mm of mercury). The driving force of ultrafiltration is opposed by oncotic pressure of blood plasma proteins (about 25 mm of mercury) and hydrostatic pressure in the cavity of the capsule of ultrafiltrate (about 15 mm of mercury). The driving force of ultrafiltration is about: 70 – (25 15) = 30 (mm of mercury); and it is called the effective filtration pressure. The energy of ATP in the process of ultrafiltration is not used.
Lowering blood pressure and / or increased hydrostatic pressure in the cavity of the capsule can lead to a slowdown, while significant changes and a complete cessation of the formation of primary urine (anuria). Approximately 1500 liters of blood pass through the kidneys with the formation of about 180 liters of primary urine (125 ml/min) per day.
Filtration ability of the kidneys is evaluated by calculating the filtration clearance (coefficient of purification) – for this, substances are injected into the blood that are only filtered but not reabsorbed or secreted (mannitol, creatinine, polysaccharide inulin).
Filtration clearance is the volume of blood plasma, which is completely cleared from the nonreabsorptable substances for 1 min. Filtration clearance (FC) is calculated as follows:
FC = (A-urine × V) / A-blood
where: A-urine is the concentration of substances in the urine, the A-blood – the concentration of substances in the blood; V – the rate of formation of urine in ml/min. In a healthy person FC is about 125 ml/min.
Primary urine, which contains all the low molecular weight components of blood and a small amount of low molecular weight proteins, is subjected to reabsorption in the proximal tubule.
2. Reabsorption is a movement of substances from the lumen of the tubule into the blood. Almost all the proteins got in the ultrafiltrate, and other substances necessary for organism are subjected to reabsorption. Therefore, daily losses of protein and peptide components of urine do not exceed 100-150 mg/day, although to 8-10 grams of protein per day can be filtered to the primary urine. 85% of the ultrafiltrate is reabsorbed in the proximal tubule. About 99% of water is also reabsorbed there; the same situation with the nutrients (glucose, amino acids), many minerals, and partially with the end products of nitrogen metabolism (urea, uric acid).
There are two mechanisms of reabsorption: simple diffusion and active transport. By active transport, Na ions are reabsorbed with sodium pump – the membrane enzyme Na, K-dependent ATPase. Many substances such as glucose and amino acids are reabsorbed in the complex with ions of Na, i.e. energy for the transport of these compounds is released as a result of the ATPase action. Reabsorption of calcium and magnesium occurs similarly. This process involves Ca2+, Mg2+-dependent ATPase. In addition to ATPase, active transport processes involves specific transport carrier proteins, called translocases. They have the ability to selectively bind to a substance that is reabsorbed, and have a limit of capacity (level of saturation of protein). Limit of kidney working capacity is determined by the limiting concentration of reabsorbed substance from the primary urine. This quantity is called the renal threshold for reabsorption (RTR). RTR is the lowest concentration of reabsorbed substance at which we have the transport maximum of reabsorption (Tmax). Tmax characterizes the state of the renal tubules and is equal to the rate of transport of substance by the transfer protein in its saturation with the substance being transported. Thus, for glucose, for example, RTR is 12.10 mg/dl. In normal glucose concentration in blood, transport systems are not fully saturated with glucose, so glucose does not appear in the urine, i.e. it is completely reabsorbed.
Isotranslocases are different from each other by Michaelis constant (Km) like isozymes. For example, early proximal tubule, where the translocases with Km = 6 mmol/l is situated, the glucose concentration is high in the filtrate. At the end of the proximal part, where most of the glucose is reabsorbed, Km of translocases is 0.35 mmol/liter. With these translocases having different affinities for glucose, almost all glucose is reabsorbed from the primary urine. 179 liters of water, about 1 kg of NaC1; about 340 g NaHCO3; about 170 g of glucose, etc. are reabsorbed per day.
3. Secretion. Tubular selective secretion is similar to reabsorption, but goes in the opposite direction: from the blood into the tubules lumen. Secretion occurs mainly in the distal tubule. The process of secretion as well as the process of reabsorption takes place with an expenditure of ATP (active transport) and is characterized by the value of transport maximum (tubular maximum). This value may serve to characterize carrier proteins, providing transport of substances. Frequently the reabsorption and secretion occur simultaneously – for example, the secretion of K+ occurs under the influence of Na+, K+-dependent ATPase. The difference is that K+ is secreted, but Na+ is reabsorbed Na. H+ and NH4+ are also secreted. The secretion rate can be identified by excretion of different dyes with the urine from the body, which can be only secreted by the kidneys secretion. To do this, dyes must be pre-entered into the blood.
As a result, the daily secondary urine volume is between 1,000 and 2,000 ml, in which the following elements are dissolved: from 12 to 6g of urea, about 1g of creatinine, approximately 1g of ammonium salts, approximately 0.5-1.0g of other products of nitrogen exchange (normally the urine may contain creatine, hippuric acid, indican and pigments); about 5-7g of mineral salts, products of detoxification of toxic compounds (in small amounts).
There is the maintenance of water and salt balance and acid-base balance in process of the kidney excretory function.
7.2. Homeostatic function of the kidneys
The water in the body is distributed between two spaces: the intracellular and extracellular. Water distribution depends on the total amount of dissolved substances, as water moves in the direction of the osmotic gradient. Kidneys are involved in maintaining a constant amount of water by affecting the ionic composition of intra- and extracellular fluids. About 75% of sodium, chloride and water are reabsorbed from the glomerular filtrate in the proximal tubule due to the ATPase mechanism. At the same time only sodium ions are actively reabsorbed; anions move through electrochemical gradient, and water is reabsorbed passively, and isoosmotically.
Kidneys are involved in regulation of acid-base balance. Maintaining of constant pH of blood is ensured through the participation of the kidneys and blood buffer systems in this process. Blood buffer systems do not eliminate the violations of the acid-alkaline balance in the body, while regulating the pH of blood in a considerable range. The kidneys are able to provide the removal of acidic or alkaline components and thereby normalize the ratio of the components of buffer systems. The change of the pH of the blood and urine may be related to human nutrition. Because acidosis is particular dangerous for the body, there are special mechanisms in the kidneys to combat it – it is the secretion of H+, ammoniogenesis and gluconeogenesis.
H+ secretion.This mechanism involves the CO2 formation in the metabolic reactions that occurs in cells of the distal tubule. Then H2CO3 is formed under the action of carbonic anhydrase. It dissociates into H+ and HCO3- and exchanges H+ ions on Na+. Then, sodium and bicarbonate ions diffuse into the blood, providing its alkalinization.
Ammoniogenesis. Activity of ammoniagenesis enzymes in the kidneys is particularly high in acidosis. Ammoniagenesis enzymes are glutaminase and glutamate dehydrogenase:
Gluconeogenesis. It occurs in the liver and kidneys. The key enzyme of this process is kidney pyruvate carboxylase. This enzyme is the most active in the acidic environment in contrast to the same liver enzyme. Therefore, pyruvate carboxylase is activated in kidneys in acidosis. Acidreacting substances (lactate, pyruvate) are beginning to turn more rapidly into glucose, which has no acidic properties. This mechanism is important in the acidosis associated with starvation. The accumulation of ketone bodies stimulates gluconeogenesis. And it helps to improve the acid-base balance and also provides the body glucose. At full starvation, 50% of glucose is produced in the kidneys.
At alkalosis, gluconeogenesis is inhibited (pyruvate carboxylase activity is decreased as a result pH change); the secretion of protons is decreased, but glycolysis and formation of pyruvate and lactate are increased.
7.3. Metabolic functions of the kidneys
1. Formation of the vitamin D3 active form. In kidneys, the final stage of maturation of the vitamin D3 active form (1, 25-dioxycholecalciferol) is a result of microsomal oxidation. It is synthesized from cholesterol in the skin under ultraviolet rays, and then hydroxylated: first in the liver (position 25), and then in kidneys (in position 1). Thus, participating in the formation of the active form of vitamin D3, kidneys have an influence on calcium and phosphorus metabolism in the body. Therefore, in kidney diseases, osteodystrophy can be developed when the processes of vitamin D3 hydroxylation are broken.
2. Erythropoiesis regulation. Glycoprotein produced in kidneys is called the renal erythropoietic factor (erythropoietin, EPO). It is a hormone that can affect the stem cells of red bone marrow. EPO directs the development of these cells towards erythropoiesis, i.e. it stimulates the formation of red blood cells. Release rate of EPO depends on supporting the kidneys with oxygen. If the amount of incoming oxygen is reduced, it increases the production of EPO. It leads to an increase in the number of erythrocytes and improves oxygen supply. Therefore, renal anemia is sometimes observed in renal diseases.
3. Protein biosynthesis. Kidneys provide active processes of protein biosynthesis that are required to other tissues. The components of the blood coagulation system, complement system and fibrinolysis system are also synthesized here.
Renin-angiotensin-aldosterone system. Protein reninis synthesized in the cells of juxtaglomerular apparatus (JGA). It is a proteolytic enzyme that is involved in regulation of vascular tone, converting angiotensinogen to angiotensin-I by partial proteolysis. Octapeptide angiotensin-II is formed from angiotensin-I under the influence of the enzyme carboxycathepsin (also by partial proteolysis). It has a vasoconstrictor effect, but also stimulates the production of adrenal cortex hormone aldosterone. Aldosterone increases the reabsorption of sodium and water in the renal tubules. It leads to an increase in the volume of blood circulating in the blood vessels. As a result blood pressure (BP) is increased. When a molecule of angiotensin-II performs its function, it is subjected to total proteolysis by the action of the special proteases – angiotensinases.
The renin production depends on the blood supply to the kidneys. Therefore, the production of renin is increased at lower blood pressure and at higher blood pressure is decreased. In the renal pathology sometimes the increased production of renin is observed, and persistent hypertension (increased blood pressure) may be developed.
Renin-angiotensin-aldosterone system functions closely with kallikrein-kinin system (another system of regulation of vascular tone); the effect of which leads to a decrease in blood pressure.
Protein kininogen is synthesized in the kidney. Entered the blood, kininogen under the influence of serine proteases – kallikreins – becomes vasoaktive peptides kinins: bradykinin and kallidin. Bradykinin and kallidin have a vasodilating effect. They are decrease blood pressure. Inactivation of kinins occurs with the participation of carboxycathepsin. This enzyme simultaneously affects both system of regulation of vascular tone, and this influence leads to increased blood pressure. Inhibitors of carboxycathepsin are used for therapeutic purposes in treating some forms of hypertension. Participation of the kidneys in the regulation of blood pressure is also connected with the production of prostaglandins, which have a hypertensive effect.
4. Catabolism of proteins. Kidneys are involved in the catabolism of some proteins with low molecular weight (5-6 kDa), and peptides that are filtered into the primary urine. There are also hormones and other biologically active substances among these proteins. In the cells of the tubules under the influence of lysosomal proteases, these proteins and peptides are hydrolyzed to amino acids, which enter the bloodstream and be reutilized by cells of other tissues.
High costs of ATP by the kidneys are associated with the processes of active transport in the reabsorption, secretion, as well as the biosynthesis of proteins. The main way of ATP synthesis is oxidative phosphorylation. Therefore, kidney tissue needs substantial quantities of oxygen. Kidney mass is 0.5% of total body mass and oxygen consumption of kidney is 10% of the incoming oxygen.
7.4. Regulation of water and salt metabolism and uropoiesis
Urine volume and ion content in it is regulated by the combined action of hormones and renal structural features. The daily urine volume is influenced by hormones aldosterone and vasopressin.
Aldosterone is a steroid hormone of the adrenal cortex. It belongs to mineralocorticoids. Aldosteron provides increased sodium reabsorption in the distal renal tubule by active transport. It is actively secreted by a significant decreasing of sodium concentration in blood plasma. Almost complete removal of sodium from the urine can occur in the case of very low concentrations of sodium in the blood plasma under the action of aldosterone. Increased sodium reabsorption leads to water retention in the body. Hypersecretion of aldosterone (hyperaldosteronism) results in sodium and water retention and leads to edema and hypertension, even heart failure. Insufficiency of aldosterone leads to a significant loss of sodium, chloride and water. The volume of blood plasma is decreased. In the kidneys, the processes of secretion of H+ and NH4+ are disturbed. It can lead to acidosis.
Vasopressin (antidiuretic hormone, ADH) is a peptide hormone synthesized in the hypothalamus and secreted from the neurohypophysis. It has a membrane mechanism of action. This mechanism is realized through the adenylatecyclase system in target cells. Vasopressin secretion increases with increasing osmotic pressure of blood plasma, for example, with an increase in salt intake or dehydration. Vasopressin causes peripheral vasoconstriction (arterioles), resulting in increased blood pressure. In the kidney, vasopressin increases the rate of water reabsorption. As a result, the relative concentrations of Na, C1, P and total N are increased. Vasopressin secretion increases with increasing osmotic pressure of blood plasma, for example, with an increase in salt intake or dehydration. It is believed that the action of vasopressin is associated with phosphorylation of proteins of apical membrane of the kidney, thus increasing its permeability. In the pituitary gland lesions, in the case of abnormal vasopressin secretion, diabetes insipidus is observed – a sharp increase in urine volume (4-5 liters) with a low specific gravity.
Parathhormone is parathyroid hormone of peptide nature (membrane mechanism of action via cAMP); it also affects the excretion of salts from the body. In the kidney, it increases the tubular reabsorption of Ca2+ and Mg2+, increases the excretion of K+, phosphate, HCO3- and decreases the excretion of H+ and NH4+. This is mainly due to reduced tubular reabsorption of phosphate. At the same time calcium concentration in plasma is increased. Hyposecretion of parathyroid hormone leads to the opposite phenomenon – an increase of phosphate in the blood plasma and to decrease the content of Ca2+ in the plasma.
Estradiol is a female sex hormone. It stimulates the synthesis of 1,25-dihydroxy vitamin D3; it increases the reabsorption of calcium and phosphorus in the kidney tubules.
Natriuretic factor (NFE, atrial natriuretic peptide (ANP), atriopeptin) is a peptide, which is formed in the cells of the atrium in the hypothalamus. This is hormone-like substance. Its targets are the cells of the distal renal tubules. It operates through guanilatcyclase messenger system, i.e. cGMP is its intracellular mediator. The result of the influence of NFE on tubular cells is a reduction of reabsorption of Na, i.e. natriuria develops.
The retention of a certain amount of water in the body is caused by adrenal hormones – aldosterone and cortisone. In this case, we have the retention of Na ions in the body and as a result – water retention. Hormone thyroxine leads to a decrease of the body weight due to enhanced excretion of water, mainly through the skin.
These mechanisms are controlled by the CNS. In the regulation of water metabolism diencephalon and gray tuber of the brain are involved. Excitation of the cerebral cortex leads to changes in the kidneys as a result of a direct transmission of the impulses along nerve pathways, or by bringing some of the endocrine glands, particularly the pituitary gland.
Disturbances of water balance in various pathological conditions may lead either to water retention in the body, or to a partial dehydration of tissues. If water retention in the tissues is of a chronic nature, it usually leads to development of various forms of edema (inflammatory, salt, and hunger).
Abnormal tissue dehydration is usually caused by increased excreation of water through the kidney (up to 15-20 liters of urine a day). This increased urination, accompanied by strong thirst, observed in diabetes insipidus. Patients, suffering from diabetes insipidus on the basis of lack of vasopressin, lose their ability to concentrate the primary urine; the urine becomes very dilute and has a low specific gravity. However, the restriction of drinking in this disease can lead to tissue dehydration incompatible with the life.
1. What is the difference of the terms "water and salt metabolism" and "mineral metabolism"?
2. What are the main parameters of the water environment of the body?
3. Specify the function of microelements in the human body.
4. Describe the excretory function of the kidneys.
5. What is the homeostatic function of the kidneys?
6. What metabolic functions do the kidneys perform?
7. What hormones are involved in the regulation of osmotic pressure and extracellular fluid volume?
8. Describe the mechanism of action of the renin-angiotensin system.