What do the kidneys provide? Metabolic changes in the kidneys, what are they? The mechanism of urine formation.
The kidneys are a veritable biochemical laboratory in which many different processes take place. As a result of chemical reactions occurring in the kidneys, they ensure the release of the body from waste products, and also participate in the formation of substances we need.
Biochemical processes in the kidneys
These processes can be divided into three groups:
1. Processes of urine formation,
2. Release of certain substances,
3. Regulation of the production of substances necessary to maintain water-salt and acid-base balance.
In connection with these processes, the kidneys perform the following functions:
- Excretory function (removal of substances from the body),
- Homeostatic function (maintaining body balance),
- Metabolic function (participation in metabolic processes and synthesis of substances).
All these functions are closely interconnected, and a failure in one of them can lead to disruption of the others.
Excretory function of the kidneys
This function is associated with the formation of urine and its removal from the body. As blood passes through the kidneys, urine is formed from plasma components. At the same time, the kidneys can regulate its composition depending on the specific state of the body and its needs.
The kidneys are excreted from the body through urine:
- Products of nitrogen metabolism: uric acid, urea, creatinine,
- Excess substances, such as water, organic acids, hormones,
- Foreign substances, for example, drugs, nicotine.
The main biochemical processes that ensure the kidneys perform their excretory function are ultrafiltration processes. Blood enters the cavity of the renal glomeruli through the renal vessels, where it passes through 3 layers of filters. As a result, primary urine is formed. Its quantity is quite large, and it still contains substances necessary for the body. Next, it enters for additional processing in the proximal tubules, where it undergoes reabsorption.
Reabsorption is the movement of substances from the tubule into the blood, that is, their return back from primary urine. On average, a person’s kidneys produce up to 180 liters of primary urine per day, and only 1-1.5 liters of secondary urine are excreted. It is this amount of excreted urine that contains everything that needs to be removed from the body. Substances such as proteins, amino acids, vitamins, glucose, some trace elements, and electrolytes are reabsorbed. First of all, water is reabsorbed, and with it the dissolved substances are returned. Thanks to the complex filtration system in a healthy body, proteins and glucose do not enter the urine, that is, their detection in laboratory tests indicates trouble and the need to determine the cause and treatment.
Homeostatic kidney function
Thanks to this function, the kidneys maintain water-salt and acid-base balance in the body.
The basis for regulating the water-salt balance is the amount of incoming fluid and salts, the amount of urine excreted (that is, liquid with salts dissolved in it). With an excess of sodium and potassium, osmotic pressure increases, because of this, osmotic receptors are irritated, and a person becomes thirsty. The volume of fluid excreted is reduced, and the concentration of urine increases. With excess fluid, blood volume increases, salt concentration decreases, and osmotic pressure drops. This is a signal for the kidneys to work more actively to remove excess water and restore balance.
The process of maintaining normal acid-base balance (pH) is carried out by the buffer systems of the blood and kidneys. Changing this balance in one direction or another leads to changes in kidney function. The process of adjusting this indicator consists of two parts.
Firstly, this is a change in the composition of urine. So, with an increase in the acidic component of the blood, the acidity of the urine also increases. An increase in the content of alkaline substances leads to the formation of alkaline urine.
Secondly, when the acid-base balance changes, the kidneys secrete substances that neutralize excess substances that lead to imbalance. For example, with increasing acidity, the secretion of H+, the enzymes glutaminase and glutamate dehydrogenase, and pyruvate carboxylase increases.
The kidneys regulate phosphorus-calcium metabolism, so if their functions are impaired, the musculoskeletal system may suffer. This metabolism is regulated through the formation of the active form of vitamin D3, which is first formed in the skin, and then hydroxylated in the liver, and then, finally, in the kidneys.
The kidneys produce a glycoprotein hormone called erythropoietin. It acts on bone marrow stem cells and stimulates the formation of red blood cells from them. The speed of this process depends on the amount of oxygen entering the kidneys. The less it is, the more actively erythropoietin is formed in order to provide the body with oxygen thanks to the greater number of red blood cells.
Another important component of kidney metabolic function is the renin-angiotensin-aldosterone system. The enzyme renin regulates vascular tone and converts angiotensinogen through multistep reactions into angiotensin II. Angiotensin II has a vasoconstrictor effect and stimulates the production of aldosterone by the adrenal cortex. Aldosterone, in turn, increases the reabsorption of sodium and water, which increases blood volume and blood pressure.
Thus, blood pressure depends on the amount of angiotensin II and aldosterone. But this process works as if in a circle. The production of renin depends on the blood supply to the kidneys. The lower the pressure, the less blood flows into the kidneys and the more renin is produced, and therefore angiotensin II and aldosterone. In this case, the pressure increases. With increased pressure, less renin is formed, and accordingly the pressure decreases.
Since the kidneys are involved in many processes in our body, problems that arise in their work inevitably affect the condition and functioning of various systems, organs and tissues.
The kidneys are involved in the metabolism of proteins, lipids and carbohydrates. This function is due to the participation of the kidneys in ensuring the constant concentration of a number of physiologically significant organic substances in the blood. Low molecular weight proteins and peptides are filtered in the renal glomeruli. In the proximal nephron they are broken down into amino acids or dipeptides and transported across the basal plasma membrane into the blood. With kidney disease, this function may be impaired. The kidneys are capable of synthesizing glucose (gluconeogenesis). During prolonged fasting, the kidneys can synthesize up to 50% of the total amount of glucose produced in the body and entering the blood. The kidneys can use glucose or free fatty acids for energy expenditure. When the level of glucose in the blood is low, kidney cells consume fatty acids to a greater extent; with hyperglycemia, glucose is predominantly broken down. The importance of the kidneys in lipid metabolism is that free fatty acids can be included in the composition of triacylglycerol and phospholipids in the kidney cells and enter the blood in the form of these compounds.
Regulation of kidney activity
From a historical perspective, experiments carried out with irritation or transection of the efferent nerves innervating the kidneys are of interest. Under these influences, diuresis changed slightly. It changed little if the kidneys were transplanted to the neck and the kidney artery was sutured to the carotid artery. However, even under these conditions it was possible to develop conditioned reflexes to painful stimulation or to water load, and diuresis also changed under unconditioned reflex influences. These experiments gave reason to assume that reflex influences on the kidneys are carried out not so much through the efferent nerves of the kidneys (they have relatively little effect on diuresis), but that a reflex release of hormones (ADH, aldosterone) occurs and they have a direct effect on the process of diuresis in the kidneys. Therefore, there is every reason to distinguish the following types in the mechanisms of regulation of urine formation: conditioned reflex, unconditioned reflex and humoral.
The kidney serves as an executive organ in a chain of various reflexes that ensure the constancy of the composition and volume of fluids in the internal environment. The central nervous system receives information about the state of the internal environment, signals are integrated and the regulation of kidney activity is ensured. Anuria that occurs with painful stimulation can be reproduced by a conditioned reflex. The mechanism of pain anuria is based on irritation of the hypothalamic centers that stimulate the secretion of vasopressin by the neurohypophysis. Along with this, the activity of the sympathetic part of the nervous system and the secretion of catecholamines by the adrenal glands increase, which causes a sharp decrease in urination due to both a decrease in glomerular filtration and an increase in tubular reabsorption of water.
Not only a decrease, but also an increase in diuresis can be caused by a conditioned reflex. Repeated introduction of water into the dog's body in combination with the action of a conditioned stimulus leads to the formation of a conditioned reflex, accompanied by an increase in urination. The mechanism of conditioned reflex polyuria in this case is based on the fact that impulses are sent from the cerebral cortex to the hypothalamus and the secretion of ADH decreases. Impulses arriving through adrenergic fibers stimulate sodium transport, and through cholinergic fibers they activate the reabsorption of glucose and the secretion of organic acids. The mechanism of changes in urine formation with the participation of adrenergic nerves is due to the activation of adenylate cyclase and the formation of cAMP in tubular cells. Catecholamine-sensitive adenylate cyclase is present in the basolateral membranes of the cells of the distal convoluted tubule and the initial sections of the collecting ducts. The afferent nerves of the kidney play a significant role as an information link in the ionic regulation system and ensure the implementation of reno-renal reflexes. As for the humoral-hormonal regulation of urine formation, this was described in detail above.
Prepared by Kasymkanov N.U.
Astana 2015
The main function of the kidneys is to remove water and water-soluble substances (end products of metabolism) from the body (1). The function of regulating the ionic and acid-base balance of the internal environment of the body (homeostatic function) is closely related to the excretory function. 2). Both functions are controlled by hormones. In addition, the kidneys perform an endocrine function, being directly involved in the synthesis of many hormones (3). Finally, the kidneys are involved in intermediary metabolism (4), especially gluconeogenesis and the breakdown of peptides and amino acids (Fig. 1).
A very large volume of blood passes through the kidneys: 1500 liters per day. From this volume, 180 liters of primary urine are filtered. Then the volume of primary urine decreases significantly due to the reabsorption of water, resulting in a daily urine output of 0.5-2.0 liters.
Excretory function of the kidneys. The process of urine formation
The process of urine formation in nephrons consists of three stages.
Ultrafiltration (glomerular or glomerular filtration). In the glomeruli of renal corpuscles, primary urine is formed from blood plasma in the process of ultrafiltration, isosmotic with blood plasma. The pores through which the plasma is filtered have an effective average diameter of 2.9 nm. With this pore size, all blood plasma components with a molecular weight (M) of up to 5 kDa freely pass through the membrane. Substances with M< 65 кДа частично проходят через поры, и только крупные молекулы (М >65 kDa) are retained by the pores and do not enter the primary urine. Since most blood plasma proteins have a fairly high molecular weight (M > 54 kDa) and are negatively charged, they are retained by the glomerular basement membrane and the protein content in the ultrafiltrate is insignificant.
Reabsorption. Primary urine is concentrated (approximately 100 times its original volume) by reverse filtration of the water. At the same time, according to the active transport mechanism, almost all low molecular weight substances are reabsorbed in the tubules, especially glucose, amino acids, as well as most electrolytes - inorganic and organic ions (Figure 2).
Reabsorption of amino acids is carried out using group-specific transport systems (carriers).
Calcium and phosphate ions. Calcium ions (Ca 2+) and phosphate ions are almost completely reabsorbed in the renal tubules, and the process occurs with the expenditure of energy (in the form of ATP). The yield for Ca 2+ is more than 99%, for phosphate ions - 80-90%. The extent of reabsorption of these electrolytes is regulated by parathyroid hormone (parathyrin), calcitonin and calcitriol.
The peptide hormone parathyrin (PTH), secreted by the parathyroid gland, stimulates the reabsorption of calcium ions and simultaneously inhibits the reabsorption of phosphate ions. In combination with the action of other bone and intestinal hormones, this leads to an increase in the level of calcium ions in the blood and a decrease in the level of phosphate ions.
Calcitonin, a peptide hormone from the C cells of the thyroid gland, inhibits the reabsorption of calcium and phosphate ions. This leads to a decrease in the level of both ions in the blood. Accordingly, with regard to the regulation of calcium ion levels, calcitonin is an antagonist of parathyrin.
The steroid hormone calcitriol, produced in the kidneys, stimulates the absorption of calcium and phosphate ions in the intestine, promotes bone mineralization, and is involved in the regulation of the reabsorption of calcium and phosphate ions in the renal tubules.
Sodium ions. Reabsorption of Na + ions from primary urine is a very important function of the kidneys. This is a highly efficient process: about 97% Na + is absorbed. The steroid hormone aldosterone stimulates, and atrial natriuretic peptide [ANP], synthesized in the atrium, on the contrary, inhibits this process. Both hormones regulate the work of Na + /K + -ATPase, localized on that side of the plasma membrane of tubule cells (distal and collecting ducts of the nephron), which is washed by blood plasma. This sodium pump pumps Na+ ions from primary urine into the blood in exchange for K+ ions.
Water. Water reabsorption is a passive process in which water is absorbed in an osmotically equivalent volume along with Na + ions. In the distal nephron, water can only be absorbed in the presence of the peptide hormone vasopressin (antidiuretic hormone, ADH), secreted by the hypothalamus. ANP inhibits water reabsorption. i.e., it enhances the removal of water from the body.
Due to passive transport, chlorine ions (2/3) and urea are absorbed. The degree of reabsorption determines the absolute amount of substances remaining in the urine and excreted from the body.
Reabsorption of glucose from primary urine is an energy-dependent process associated with ATP hydrolysis. At the same time, it is accompanied by concomitant transport of Na + ions (along a gradient, since the concentration of Na + in primary urine is higher than in cells). Amino acids and ketone bodies are also absorbed by a similar mechanism.
The processes of reabsorption and secretion of electrolytes and non-electrolytes are localized in various parts of the renal tubules.
Secretion. Most substances to be excreted from the body enter the urine through active transport in the renal tubules. These substances include H + and K + ions, uric acid and creatinine, and drugs such as penicillin.
Organic constituents of urine:
The main part of the organic fraction of urine consists of nitrogen-containing substances, the end products of nitrogen metabolism. Urea produced in the liver. is a carrier of nitrogen contained in amino acids and pyrimidine bases. The amount of urea is directly related to protein metabolism: 70 g of protein leads to the formation of ~30 g of urea. Uric acid serves as the end product of purine metabolism. Creatinine, which is formed due to the spontaneous cyclization of creatine, is the end product of metabolism in muscle tissue. Since daily creatinine excretion is an individual characteristic (it is directly proportional to muscle mass), creatinine can be used as an endogenous substance to determine glomerular filtration rate. The content of amino acids in urine depends on the nature of the diet and the efficiency of the liver. Amino acid derivatives (for example, hippuric acid) are also present in the urine. The content in the urine of derivatives of amino acids that are part of special proteins, for example, hydroxyproline, present in collagen, or 3-methylhistidine, which is part of actin and myosin, can serve as an indicator of the intensity of the breakdown of these proteins.
The constituent components of urine are conjugates formed in the liver with sulfuric and glucuronic acids, glycine and other polar substances.
Products of metabolic transformation of many hormones (catecholamines, steroids, serotonin) may be present in the urine. Based on the content of the final products, one can judge the biosynthesis of these hormones in the body. The protein hormone choriogonadotropin (CG, M 36 kDa), formed during pregnancy, enters the blood and is detected in the urine by immunological methods. The presence of the hormone serves as an indicator of pregnancy.
Urochromes, derivatives of bile pigments formed during the degradation of hemoglobin, give the yellow color to urine. Urine darkens during storage due to oxidation of urochromes.
Inorganic constituents of urine (Figure 3)
The urine contains Na +, K +, Ca 2+, Mg 2+ and NH 4 + cations, Cl - anions, SO 4 2- and HPO 4 2- and other ions in trace amounts. The content of calcium and magnesium in feces is significantly higher than in urine. The amount of inorganic substances largely depends on the nature of the diet. With acidosis, ammonia excretion may greatly increase. The excretion of many ions is regulated by hormones.
Changes in the concentration of physiological components and the appearance of pathological components of urine are used to diagnose diseases. For example, in diabetes, glucose and ketone bodies are present in the urine (Appendix).
4. Hormonal regulation of urine formation
The volume of urine and the content of ions in it are regulated due to the combined action of hormones and the structural features of the kidney. The volume of daily urine is influenced by hormones:
ALDOSTERONE and VASOPRESSIN (their mechanism of action was discussed earlier).
PARATHORMONE - a parathyroid hormone of a protein-peptide nature (membrane mechanism of action, through cAMP) also affects the removal of salts from the body. In the kidneys, it enhances the tubular reabsorption of Ca +2 and Mg +2, increases the excretion of K +, phosphate, HCO 3 - and reduces the excretion of H + and NH 4 +. This is mainly due to a decrease in tubular reabsorption of phosphate. At the same time, the concentration of calcium in the blood plasma increases. Hyposecretion of parathyroid hormone leads to the opposite phenomena - an increase in the phosphate content in the blood plasma and a decrease in the Ca + 2 content in the plasma.
ESTRADIOL is a female sex hormone. Stimulates the synthesis of 1,25-dioxyvitamin D 3, enhances the reabsorption of calcium and phosphorus in the renal tubules.
Homeostatic kidney function
1) water-salt homeostasis
The kidneys are involved in maintaining a constant amount of water by influencing the ionic composition of intra- and extracellular fluids. About 75% of sodium, chlorine and water ions are reabsorbed from the glomerular filtrate in the proximal tubule due to the mentioned ATPase mechanism. In this case, only sodium ions are actively reabsorbed, anions move due to the electrochemical gradient, and water is reabsorbed passively and isosmotically.
2) participation of the kidneys in the regulation of acid-base balance
The concentration of H + ions in plasma and in the intercellular space is about 40 nM. This corresponds to a pH value of 7.40. The pH of the internal environment of the body must be maintained constant, since significant changes in the concentration of runs are not compatible with life.
The constancy of the pH value is maintained by plasma buffer systems, which can compensate for short-term disturbances in the acid-base balance. Long-term pH equilibrium is maintained through the production and removal of protons. If there are disturbances in the buffer systems and if the acid-base balance is not maintained, for example as a result of kidney disease or disruptions in the frequency of breathing due to hypo- or hyperventilation, the plasma pH value goes beyond acceptable limits. A decrease in pH value of 7.40 by more than 0.03 units is called acidosis, and an increase is called alkalosis.
Origin of protons. There are two sources of protons - free acids in food and sulfur-containing amino acids in proteins obtained from food. Acids, such as citric, ascorbic and phosphoric, release protons in the intestinal tract (at an alkaline pH). The amino acids methionine and cysteine formed during the breakdown of proteins make the greatest contribution to ensuring the balance of protons. In the liver, the sulfur atoms of these amino acids are oxidized to sulfuric acid, which dissociates into sulfate ions and protons.
During anaerobic glycolysis in muscles and red blood cells, glucose is converted into lactic acid, the dissociation of which leads to the formation of lactate and protons. The formation of ketone bodies - acetoacetic and 3-hydroxybutyric acids - in the liver also leads to the release of protons; an excess of ketone bodies leads to an overload of the plasma buffer system and a decrease in pH (metabolic acidosis; lactic acid → lactic acidosis, ketone bodies → ketoacidosis). Under normal conditions, these acids are usually metabolized to CO 2 and H 2 O and do not affect proton balance.
Since acidosis poses a particular danger to the body, the kidneys have special mechanisms to combat it:
a) secretion of H +
This mechanism includes the process of formation of CO 2 in metabolic reactions occurring in the cells of the distal tubule; then the formation of H 2 CO 3 under the action of carbonic anhydrase; its further dissociation into H + and HCO 3 - and the exchange of H + ions for Na + ions. Sodium and bicarbonate ions then diffuse into the blood, causing it to become alkaline. This mechanism has been tested experimentally - the introduction of carbonic anhydrase inhibitors leads to increased sodium loss in secondary urine and acidification of urine stops.
b) ammoniogenesis
The activity of ammoniogenesis enzymes in the kidneys is especially high under conditions of acidosis.
Ammoniogenesis enzymes include glutaminase and glutamate dehydrogenase:
c) gluconeogenesis
It occurs in the liver and kidneys. The key enzyme of the process is renal pyruvate carboxylase. The enzyme is most active in an acidic environment - this is how it differs from the same liver enzyme. Therefore, during acidosis in the kidneys, carboxylase is activated and acid-reacting substances (lactate, pyruvate) more intensively begin to convert into glucose, which does not have acidic properties.
This mechanism is important in acidosis associated with fasting (from a lack of carbohydrates or from a general lack of nutrition). The accumulation of ketone bodies, which are acidic in properties, stimulates gluconeogenesis. And this helps improve the acid-base state and at the same time supplies the body with glucose. During complete fasting, up to 50% of blood glucose is formed in the kidneys.
With alkalosis, gluconeogenesis is inhibited (as a result of changes in pH, PVK carboxylase is inhibited), proton secretion is inhibited, but at the same time glycolysis is enhanced and the formation of pyruvate and lactate increases.
Metabolic kidney function
1) Formation of the active form of vitamin D 3. In the kidneys, as a result of the microsomal oxidation reaction, the final stage of maturation of the active form of vitamin D 3 - 1,25-dioxycholecalciferol - occurs. The precursor of this vitamin, vitamin D 3, is synthesized in the skin, under the influence of ultraviolet rays from cholesterol, and then hydroxylated: first in the liver (at position 25), and then in the kidneys (at position 1). Thus, by participating in the formation of the active form of vitamin D 3, the kidneys influence phosphorus-calcium metabolism in the body. Therefore, in case of kidney diseases, when the processes of hydroxylation of vitamin D 3 are disrupted, OSTEODISTROPHY may develop.
2) Regulation of erythropoiesis. The kidneys produce a glycoprotein called renal erythropoietic factor (REF or ERYTHROPOETIN). It is a hormone that is capable of influencing red bone marrow stem cells, which are the target cells for PEF. PEF directs the development of these cells along the path of sritropoiesis, i.e. stimulates the formation of red blood cells. The rate of PEF release depends on the supply of oxygen to the kidneys. If the amount of incoming oxygen decreases, the production of PEF increases - this leads to an increase in the number of red blood cells in the blood and an improvement in oxygen supply. Therefore, in kidney diseases, renal anemia is sometimes observed.
3) Biosynthesis of proteins. In the kidneys, the processes of biosynthesis of proteins that are necessary for other tissues are actively taking place. Some components are synthesized here:
Blood coagulation systems;
Complement systems;
Fibrinolysis systems.
In the kidneys, RENIN is synthesized in the cells of the juxtaglomerular apparatus (JA).
The renin-angiotensin-aldosterone system works in close contact with another system for regulating vascular tone: the KALLIKREIN-KININ SYSTEM, the action of which leads to a decrease in blood pressure.
The protein kininogen is synthesized in the kidneys. Once in the blood, kininogen, under the action of serine proteinases - kallikreins, is converted into vasoactive peptides - kinins: bradykinin and kallidin. Bradykinin and kallidin have a vasodilating effect - they lower blood pressure. Inactivation of kinins occurs with the participation of carboxycathepsin - this enzyme simultaneously affects both systems of regulation of vascular tone, which leads to an increase in blood pressure. Carboxycathepsin inhibitors are used for medicinal purposes in the treatment of certain forms of arterial hypertension (for example, the drug clofelline).
The participation of the kidneys in the regulation of blood pressure is also associated with the production of prostaglandins, which have a hypotensive effect and are formed in the kidneys from arachidonic acid as a result of lipid peroxidation reactions (LPO).
4) Protein catabolism. The kidneys are involved in the catabolism of some low molecular weight proteins (5-6 kDa) and peptides that are filtered into primary urine. Among them are hormones and some other biologically active substances. In tubular cells, under the action of lysosomal proteolytic enzymes, these proteins and peptides are hydrolyzed to amino acids, which enter the blood and are reutilized by cells of other tissues.
1. Formation of the active form of vitamin D 3. In the kidneys, as a result of microsomal oxidation, the final stage of maturation of the active form of vitamin D 3 occurs - 1,25-dihydroxycholecalciferol, which is synthesized in the skin under the influence of ultraviolet rays from cholesterol, and then hydroxylated: first in the liver (at position 25) and then in the kidneys (at position 1). Thus, by participating in the formation of the active form of vitamin D 3, the kidneys influence phosphorus-calcium metabolism in the body. Therefore, in kidney diseases, when the processes of hydroxylation of vitamin D 3 are disrupted, osteodystrophy may develop.
2. Regulation of erythropoiesis. The kidneys produce a glycoprotein called renal erythropoietic factor (PEF or erythropoietin). This is a hormone that is capable of influencing red bone marrow stem cells, which are target cells for PEF. PEF directs the development of these cells along the path of erythropoiesis, i.e. stimulates the formation of red blood cells. The rate of PEF release depends on the supply of oxygen to the kidneys. If the amount of incoming oxygen decreases, the production of PEF increases - this leads to an increase in the number of red blood cells in the blood and an improvement in oxygen supply. Therefore, in kidney diseases, renal anemia is sometimes observed.
3. Biosynthesis of proteins. In the kidneys, the processes of biosynthesis of proteins that are necessary for other tissues are actively taking place. Components of the blood coagulation system, complement system and fibrinolysis system are also synthesized here.
The kidneys synthesize the enzyme renin and the protein kininogen, which are involved in the regulation of vascular tone and blood pressure.
4. Protein catabolism. The kidneys are involved in the catabolism of some low molecular weight proteins (5-6 kDa) and peptides that are filtered into the primary urine. Among them are hormones and some other biologically active substances. In tubule cells, under the action of lysosomal proteolytic enzymes, these proteins and peptides are hydrolyzed to amino acids, which then enter the blood and are reutilized by cells of other tissues.
Large expenditures of ATP by the kidneys are associated with the processes of active transport during reabsorption, secretion, as well as with protein biosynthesis. The main pathway for producing ATP is oxidative phosphorylation. Therefore, kidney tissue needs significant amounts of oxygen. The mass of the kidneys is 0.5% of the total body weight, and the oxygen consumption of the kidneys is 10% of the total oxygen intake.
7.4. REGULATION OF WATER-SALT METABOLISM
AND URINARY
The volume of urine and the content of ions in it are regulated due to the combined action of hormones and the structural features of the kidney.
Renin-angiotensin-aldosterone system. In the kidneys, in the cells of the juxtaglomerular apparatus (JGA), renin is synthesized, a proteolytic enzyme that is involved in the regulation of vascular tone, converting angiotensinogen into the decapeptide angiotensin I through partial proteolysis. From angiotensin I, under the action of the enzyme carboxycathepsin, the octapeptide angiotensin II is formed (also by partial proteolysis). It has a vasoconstrictor effect and also stimulates the production of the adrenal cortex hormone - aldosterone.
Aldosterone is a steroid hormone of the adrenal cortex from the mineralcorticoid group, which enhances the reabsorption of sodium from the distal part of the renal tubule due to active transport. It begins to be actively secreted when the sodium concentration in the blood plasma decreases significantly. In the case of very low sodium concentrations in the blood plasma, almost complete removal of sodium from the urine can occur under the influence of aldosterone. Aldosterone enhances the reabsorption of sodium and water in the renal tubules - this leads to an increase in the volume of blood circulating in the vessels. As a result, blood pressure (BP) increases (Fig. 19).
Rice. 19. Renin-angiotensin-aldosterone system
When the angiotensin-II molecule fulfills its function, it undergoes total proteolysis under the action of a group of special prosthetics - angiotensinases.
Renin production depends on the blood supply to the kidneys. Therefore, when blood pressure decreases, renin production increases, and when blood pressure increases, it decreases. With kidney pathology, increased production of renin is sometimes observed and persistent hypertension (increased blood pressure) may develop.
Hypersecretion of aldosterone leads to sodium and water retention - then edema and hypertension develop, including heart failure. Aldosterone deficiency leads to significant loss of sodium, chloride and water and a decrease in blood plasma volume. In the kidneys, the processes of secretion of H + and NH 4 + are simultaneously disrupted, which can lead to acidosis.
The renin-angiotensin-aldosterone system works in close contact with another system regulating vascular tone kallikrein-kinin system, the action of which leads to a decrease in blood pressure (Fig. 20).
Rice. 20. Kallikrein-kinin system
The protein kininogen is synthesized in the kidneys. Once in the blood, kininogen, under the action of serine proteinases - kallikreins, is converted into vasoactin peptides - kinins: bradykinin and kallidin. Bradykinin and kallidin have a vasodilating effect - they lower blood pressure.
Inactivation of kinins occurs with the participation of carboxycathepsin - this enzyme simultaneously affects both systems of regulation of vascular tone, which leads to an increase in blood pressure (Fig. 21). Carboxycathepsin inhibitors are used for medicinal purposes in the treatment of certain forms of arterial hypertension. The participation of the kidneys in the regulation of blood pressure is also associated with the production of prostaglandins, which have a hypotensive effect.
Rice. 21. Renin-angiotensin-aldosterone relationship
and kallikrein-kinin systems
Vasopressin– a peptide hormone synthesized in the hypothalamus and secreted from the neurohypophysis, has a membrane mechanism of action. This mechanism in target cells is realized through the adenylate cyclase system. Vasopressin causes constriction of peripheral blood vessels (arterioles), resulting in an increase in blood pressure. In the kidneys, vasopressin increases the rate of water reabsorption from the initial part of the distal convoluted tubules and collecting ducts. As a result, the relative concentrations of Na, C1, P and total N increase. Vasopressin secretion increases when plasma osmotic pressure increases, for example, with increased salt intake or dehydration. It is believed that the action of vasopressin is associated with phosphorylation of proteins in the apical membrane of the kidney, resulting in an increase in its permeability. If the pituitary gland is damaged, if the secretion of vasopressin is impaired, diabetes insipidus is observed - a sharp increase in the volume of urine (up to 4-5 l) with a low specific gravity.
Natriuretic factor(NUF) is a peptide that is formed in the cells of the atrium in the hypothalamus. This is a hormone-like substance. Its targets are cells of the distal renal tubules. NUF acts through the guanylate cyclase system, i.e. its intracellular mediator is cGMP. The result of the influence of NUF on tubular cells is a decrease in Na + reabsorption, i.e. Natriuria develops.
Parathyroid hormone– parathyroid hormone of protein-peptide nature. It has a membrane mechanism of action through cAMP. Affects the removal of salts from the body. In the kidneys, parathyroid hormone enhances the tubular reabsorption of Ca 2+ and Mg 2+, increases the excretion of K +, phosphate, HCO 3 - and reduces the excretion of H + and NH 4 +. This is mainly due to a decrease in tubular reabsorption of phosphate. At the same time, the concentration of calcium in the plasma increases. Hyposecretion of parathyroid hormone leads to the opposite phenomena - an increase in the phosphate content in the blood plasma and a decrease in the Ca 2+ content in the plasma.
Estradiol– female sex hormone. Stimulates synthesis
1,25-dioxycalciferol, enhances the reabsorption of calcium and phosphorus in the renal tubules.
Adrenal hormone influences the retention of a certain amount of water in the body. cortisone. In this case, there is a delay in the release of Na ions from the body and, as a result, water retention. Hormone thyroxine leads to a drop in body weight due to increased release of water, mainly through the skin.
These mechanisms are under the control of the central nervous system. The diencephalon and gray tubercle of the brain are involved in the regulation of water metabolism. Excitation of the cerebral cortex leads to changes in the functioning of the kidneys as a result of either the direct transmission of corresponding impulses along the nerve pathways, or by excitation of certain endocrine glands, in particular the pituitary gland.
Disturbances in water balance in various pathological conditions can lead to either water retention in the body or partial dehydration of tissues. If water retention in tissues is chronic, various forms of edema usually develop (inflammatory, salt, starvation).
Pathological tissue dehydration is usually a consequence of the excretion of an increased amount of water through the kidneys (up to 15-20 liters of urine per day). Such increased urination, accompanied by extreme thirst, is observed in diabetes insipidus (diabetes insipidus). In patients suffering from diabetes insipidus due to a lack of the hormone vasopressin, the kidneys lose the ability to concentrate primary urine; the urine becomes very dilute and has a low specific gravity. However, limiting drinking during this disease can lead to tissue dehydration incompatible with life.
Control questions
1. Describe the excretory function of the kidneys.
2. What is the homeostatic function of the kidneys?
3. What metabolic function do the kidneys perform?
4. What hormones are involved in the regulation of osmotic pressure and extracellular fluid volume?
5. Describe the mechanism of action of the renin-angiotensin system.
6. What is the relationship between the renin-aldosterone-angiotensin and kallikrein-kinin systems?
7. What hormonal regulation disorders can cause hypertension?
8. Specify the reasons for water retention in the body.
9. What causes diabetes insipidus?
The kidneys are among the most well-supplied organs of the human body. They consume 8% of all blood oxygen, although their mass barely reaches 0.8% of body weight.
The cortex is characterized by an aerobic type of metabolism, the medulla is anaerobic.
The kidneys have a wide range of enzymes inherent in all actively functioning tissues. At the same time, they are distinguished by their “organ-specific” enzymes, the determination of the content of which in the blood in case of kidney disease has diagnostic value. These enzymes primarily include glycine amido-transferase (it is also active in the pancreas), which transfers the amidine group from arginine to glycine. This reaction is the initial step in creatine synthesis:
Glycine amido transferase
L-arginine + glycine L-ornithine + glycocyamine
From isoenzyme spectrum for the renal cortex, LDH 1 and LDH 2 are characteristic, and for the medulla, LDH 5 and LDH 4 are characteristic. In acute renal diseases, increased activity of the aerobic isoenzymes lactate dehydrogenase (LDH 1 and LDH 2) and the isoenzyme alanine aminopeptidase – AAP 3 is detected in the blood.
Along with the liver, the kidneys are an organ capable of gluconeogenesis. This process occurs in the cells of the proximal tubules. Main glutamine serves as a substrate for gluconeogenesis, which simultaneously performs a buffer function to maintain the required pH. Activation of the key enzyme of gluconeogenesis – phosphoenolpyruvate carboxykinase – caused by the appearance of acidic equivalents in the inflowing blood . Therefore, the state acidosis leads, on the one hand, to stimulation of gluconeogenesis, on the other, to an increase in the formation of NH 3, i.e. neutralization of acidic foods. However redundant ammonia production - hyperammoniemia - will already determine the development of metabolic alkalosis. An increase in the concentration of ammonia in the blood is the most important symptom of a violation of the processes of urea synthesis in the liver.
Mechanism of urine formation.
There are 1.2 million nephrons in the human kidney. The nephron consists of several parts that differ morphologically and functionally: the glomerulus (glomerulus), proximal tubule, loop of Henle, distal tubule and collecting duct. Every day, the glomeruli filter 180 liters of supplied blood plasma. Ultrafiltration of blood plasma occurs in the glomeruli, resulting in the formation of primary urine.
Molecules with a molecular weight of up to 60,000 Da enter primary urine, i.e. There is practically no protein in it. The filtration capacity of the kidneys is judged on the basis of the clearance (purification) of a particular compound - the number of ml of plasma that can be completely freed from a given substance when it passes through the kidney (more details in the physiology course).
The renal tubules carry out the resorption and secretion of substances. This function is different for different connections and depends on each segment of the tubule.
In the proximal tubules as a result of the absorption of water and Na +, K +, Cl -, HCO 3 - ions dissolved in it. concentration of primary urine begins. Water absorption occurs passively following the actively transported sodium. The cells of the proximal tubules also reabsorb glucose, amino acids, and vitamins from primary urine.
Additional Na + reabsorption occurs in the distal tubules. Water absorption here occurs independently of sodium ions. K +, NH 4 +, H + ions are secreted into the lumen of the tubules (note that K +, unlike Na +, can not only be reabsorbed, but also secreted). In the process of secretion, potassium from the intercellular fluid enters the tubule cell through the basal plasma membrane due to the work of the “K + -Na + -pump”, and then passively, by diffusion, is released into the lumen of the nephron tubule through the apical cell membrane. In Fig. the structure of the “K + -Na+-pump”, or K + -Na + -ATPase is presented (Fig. 1)
Fig. 1 Functioning of K + -Na + -ATPase
The final concentration of urine occurs in the medullary segment of the collecting ducts. Only 1% of the fluid filtered by the kidneys turns into urine. In the collecting ducts, water is reabsorbed through embedded aquaporins II (water transport channels) under the influence of vasopressin. The daily amount of final (or secondary) urine, which has many times higher osmotic activity than primary urine, averages 1.5 liters.
The reabsorption and secretion of various compounds in the kidneys is regulated by the central nervous system and hormones. Thus, with emotional and pain stress, anuria (cessation of urination) can develop. Water absorption is increased by the action of vasopressin. Its deficiency leads to water diuresis. Aldosterone increases the reabsorption of sodium, and along with the latter, water. Parathyrine affects the absorption of calcium and phosphates. This hormone increases phosphate excretion, while vitamin D delays it.
The role of the kidneys in maintaining acid-base balance. The constancy of blood pH is maintained by its buffer systems, lungs and kidneys. The constancy of the pH of the extracellular fluid (and indirectly - intracellular) is ensured by the lungs by removing CO 2, the kidneys by removing ammonia and protons and reabsorption of bicarbonates.
The main mechanisms in the regulation of acid-base balance are the process of sodium reabsorption and the secretion of hydrogen ions formed with the participation carbanhydrase.
Carbanhydrase (Zn cofactor) accelerates the restoration of equilibrium in the formation of carbonic acid from water and carbon dioxide:
N 2 O + CO 2 ⇄ N 2 CO 3 ⇄ N + + VAT 3 –
At acidic values, the pH increases R CO2 and at the same time the concentration of CO2 in the blood plasma. CO 2 already diffuses in greater quantities from the blood into the cells of the renal tubules (). In the renal tubules, under the action of carbonic acid, carbon dioxide () is formed, dissociating into a proton and a bicarbonate ion. H + -ions are transported () into the lumen of the tubule using an ATP-dependent proton pump or by replacing them with Na +. Here they bind to HPO 4 2- to form H 2 PO 4 - . On the opposite side of the tubule (bordering the capillary), with the help of the carbonic acid reaction (), bicarbonate is formed, which, together with the sodium cation (Na + cotransport), enters the blood plasma (Fig. 2).
If carbanhydrase activity is inhibited, the kidneys lose their ability to secrete acid.
Rice. 2. The mechanism of reabsorption and secretion of ions in the kidney tubule cell
The most important mechanism contributing to the retention of sodium in the body is the formation of ammonia in the kidneys. NH3 is used in place of other cations to neutralize the acidic equivalents of urine. The source of ammonia in the kidneys is the processes of glutamine deamination and oxidative deamination of amino acids, primarily glutamine.
Glutamine is the amide of glutamic acid, formed when NH 3 is added to it by the enzyme glutamine synthase, or synthesized in transamination reactions. In the kidneys, the amide group of glutamine is hydrolytically cleaved from glutamine by the enzyme glutaminase I. This produces free ammonia:
glutaminase I
Glutamine Glutamic acid + NH 3
Glutamate dehydrogenase
α-ketoglutaric
acid + NH 3
Ammonia can easily diffuse into the renal tubules and there it is easy to attach protons to form ammonium ion: NH 3 + H + ↔NH 4 +
