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 renin is 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.