CC BY
20
UDC 616.61-002:616.379-008.64
DIABETIC NEPHROPATY. MODERN VIEW OF THE PROBLEM
Altai State Medical University, Barnaul A.Yu. Zharikov, R.O. Shchekochikhina
Diabetes mellitus (DM) is a disease that accompanies a person for a long period of time. The greatest danger of diabetes is undoubtedly associated with complications that develop due to its damaging effects on blood vessels, particularly diabetic nephropathy (DN), which develops in approximately 20.1% of patients with diabetes of the 1st type and 6.3% of patients with diabetes of the 2nd type. In patients with diabetes of the 2nd type, diabetic nephrop-athy ranks third among causes of death after diseases of the cardiovascular system and oncological pathologies. There are many mechanisms of damaging effects of various factors that play a key role in the development of renal pathology in diabetes. We focused on a more detailed examination of the effect of renin-angiotensin-aldosterone (RAAS), direct damaging effects of hyperglycemia, polyol glucose metabolism, and hyperlipidemia, endothelial growth factor (VEGF) and transforming growth factor fi (TGF-fi). Based on the knowledge of the pathogenesis of diabetic nephropathy, very promising targets have been identified for the correction of this pathology. Key words: diabetic nephropathy, kidney, diabetes, hyperglycemia, final products of glycosylation.
Diabetes mellitus (DM) is a disease that accompanies a person for a fairly long period of time. Since the appearance of this pathology and to this day, it is of interest to many researchers due to its insufficient study. Despite the successes in the treatment of diabetes, at present, unfortunately, there is an increase in the incidence of both type 1 diabetes and type 2 diabetes. According to estimates, by 2040, the number of people suffering from diabetes at the age of 20-79 will increase to 642 million [1].
The greatest danger of diabetes is certainly associated with complications that develop due to its damaging effects on blood vessels. An important place in this series is diabetic nephropathy (DN), which develops in approximately 20.1% of patients with type 1 diabetes and 6.3% of patients with type 2 diabetes [2].
In patients with type 2 diabetes, diabetic ne-phropathy ranks third among causes of death after diseases of the cardiovascular system and oncological pathologies [2].
The history of studying the problem of kidney damage in diabetes starts with the work of the British physician Richard Bright, who is the founder of the doctrine of kidney disease. He first described in 1836 that in such patients the observed pro-teinuria is a sign of renal damage [3,4,5]. In 1936, American pathologists P. Kimmelstiel and C. Wilson first described renal pathology in patients with diabetes [6].
To date, the main cause of the terminal stage of chronic kidney disease, both in Europe, in the US and Japan, is nephropathy associated with type 2 diabetes [7, 8].
Diabetic nephropathy is represented by a complex of lesions of arterioles, arteries, glomeruli and tubules of the kidney [9, 10, 11, 12, 13]. DТ is characterized by damage to kidney tissue in diabetes, which leads to the development of diffuse or 22
nodular glomerulosclerosis, which, in turn, leads to the development of chronic renal failure (CRF). It is classically accepted to distinguish three stages of diabetic nephropathy: the stage of microalbu-minuria (MAU); a stage of proteinuria (PU) with a preserved renal function and a stage of chronic renal failure (CRF) [9, 14, 15].
But the initial structural and functional changes begin to develop even before the increase in albumin excretion in the urine [16]. Modern achievements in the field of molecular medicine and experimental nephrology lead to a gradual increase in the amount of knowledge about more detailed mechanisms for the development of MAU and PU. The main role of podocytes - the main components of the slit diaphragm of the glomeruli- in these processes was proved [16, 17]. There are works that demonstrate the relationship of the growth of AU with functional disorders in podocytes [16, 18-20]. It was shown that these changes develop long before the detection of MAU and can be detected even in the short course of diabetes [21-23]. Thus, podocytes are of interest for the development of methods for inhibiting the development of DN [16]. The podocyte itself has a rather complex structure that provides a wide range of its functions and adaptive responses under physiological conditions, but in turn makes this cell very sensitive to various damaging factors. As a result of exposure to pathogenic agents (metabolic, toxic, hemodynamic), podocytes undergo structural and functional changes (this phenomenon is called "podocytopathy"). [16,17,21,24,25]. A clear sign of podocytopathy is the smoothing of the peduncles of the podocytes with a violation of the permeability of the slit diaphragm, as well as hypertrophy and cell death - apoptosis, detachment of the podo-cytes from the glomerular basement membrane (GBM) with their removal to the urinary space and the emergence of whole cells (podocytouria)
in the urine and its structural proteins, for example, nephrin. As a result of the above-described processes, the number of podocytes in the glomer-ulus decreases (podocytopenia) [16]. Podocyto-penia leads to an even greater disruption of glo-merular permeability. In the place where the loss of podocyte occurs, the GBM is exposed and fused with the Shumlyansky-Bowman capsule [16, 26]. It is proved that the loss of 20-40% of podo-cytes in the glomerulus leads to the formation of synechias with a capsule, with the loss of 4060% of podocytes, glomerulosclerosis develops, and the loss of more than 60% of these cells leads to irreversible damage of the glomerular filter with impaired renal function. [16, 27]. At present, it has been established that the so-called phenomenon of smoothing of peduncular appendices is the product of the effect of the pathogenic factor on epithelial cells. As a result of this influence, the actin cytoskeleton of the podocyte is disrupted with its transformation into a dense network, which leads to an increase in the permeability of the glomerular filter due to the displacement of the slit diaphragm and the fusion of the filtration gaps. This phenomenon was experimentally studied, a direct dependence of the expression of these changes on the degree of AU was established [16, 20-22, 28].
According to modern concepts, the main barrier of the glomerular filter for plasma proteins is the interpodocyte slit diaphragm. The complex molecular organization of the peduncular appendices of podocytes was studied. It was found that the filtration gaps are formed by special adhesive compounds, the main component of which is the transmembrane protein nephrin. It participates in binding to the actin cytoskele-ton of podocytes, and also participates in the formation of the interpodocyte slit diaphragm. With the development of DN, even before the appearance of PU, areas of destruction of the slit diaphragm corresponding to the areas of smoothened appendices of podocytes and reduced expression of nephrin are observed [16].
Pathogenesis of diabetic nephropathy
Diabetic nephropathy develops under the influence of a huge number of causes. But from the whole variety of mechanisms of development of DN, the most studied and proven are: metabolic (hyperglycemia, hyperlipidemia) and hemody-namic (intraglobular hypertension, arterial hypertension (AH)).
Hyperglycemia
Undoubtedly, one of the most important metabolic factors triggering kidney damage is hyper-glycemia. There are several ways that ultimately lead to cell death. In conditions of hyperglycemia, stable products of glycosylation (or glyoxidation, advanced glycation end product, AGE, KPG) are
formed. In the body, their auto-oxidation or interaction with cellular receptors can occur. Regenerating sugars (glucose, mannose, G-6-P, fructose), containing aldehyde groups in their structure, interact with amino groups that provide, for example, proteins, and lead to the formation of Schiff bases. A further chemical transformation, known as the Amadori rearrangement (Hodge, 1955), causes the formation of glycosylated products. As a result, the structure and function of proteins change, which, in turn, leads to the development of stable cell damage. The final products of glycosylation lead to a change in the metabolism of the body's major proteins (collagen, myelin, DNA). As a result of glycosylation of structural proteins of the basal membrane of glomeruli and mesangium, their configuration is broken, loss of charge and size-selectivity of the basal membrane of the glomer-uli and the inhibition of metabolism of the basic protein components of the kidney structures occur, which is accompanied by an increase in the volume of the mesangial matrix and thickening of the basal membrane of the vessels [9]. Also in the kidney, the KPGs formed in the basal membrane of the glomeruli are fixed with albumin, IgG, which leads to its thickening, the deposition of immune complexes in it, which entail a change in the properties and structure of the components of the glomerular matrix [9, 10, 11, 25] . Glycosylat-ed proteins or cytokines (TNF-a, interleukin-1, etc.) act on endothelial cells in such a way that they produce intensively different growth factors that accelerate cell proliferation processes, which leads to even more development of DN [29-31].
Another mechanism of the damaging effect of hyperglycemia is the decrease in the activity of enzymes that participate in the sulfation of hep-aransulfate (HS). HS of the vascular wall participates in the creation of a negative endothelial charge, while ensuring the anticoagulant properties of the vascular wall, and also regulates the proliferation of smooth muscle cells [33]. The incompletely sulfated chains of HS, built into the basal membrane of the glomerulus (BMG), do not provide sufficient negative charge, which leads to a loss of the charge-selective properties of the glomerular filter and the development of MAU. In turn, sul-fonated sulfated chains of HS on the endothelium of other vessels also lead to increased permeability of membranes and generalized endothelial dysfunction [34].
Irreversible glycosylation products circulating in blood also affect lipid metabolism. On the one hand, they glycosylate lipids, and on the other -cause their peroxide oxidation. As a result, the biological activity of lipids, their transport and cleavage due to their glycosylation are disturbed. This leads to the fact that the cells continue to receive LDL, despite the glut of cells with cholesterol. In addition, the glycosylated vascular collagen ac-
quires the ability to bind three times as much LDL cholesterol as collagen to healthy people.
Walcher D. et al. found that binding of AGE to a specific receptor for AGE (RAGE) results in the release of proinflammatory mediators in various types of vascular cells, which causes various microvascular and macrovascular complications [34, 35]. Systemic damage to the endothelium by DN by the end products of glycation leads to an increase in the permeability of the endothelial barrier for low molecular weight substances, as well as the release of procoagulant factors, which provokes thrombotic occlusion of capillaries and development of coagulopathy [9,15,36,37]. Amadori products thus disrupt intracinal hemodynamics, contributing to the maintenance of hyperfiltration [34,38].
There is also another metabolic mechanism of cell damage - the polyol pathway. Although it is in the development of diabetic nephropathy that the mechanism of polyol glucose metabolism has neither experimental nor clinical confirmation, we should dwell on this issue. Under conditions of increased glucose, polyhydric alcohol (polyol) sorbitol is formed under the action of the aldose reductase enzyme, which catalyzes the reduction of glucose to sorbitol using NADPH as a cofactor. Sorbitol is metabolized to fructose with sorbitol de-hydrogenase, increasing the ratio of NADH/NAD + [39,40]. The activity of this pathway of metabolism increases significantly in the presence of high concentrations of glucose. Under these conditions, slowly hydrolyzed and slowly diffused through cell membranes, due to high hydrophilicity, sorbitol accumulates in the cell, disrupting its homeostasis and leading to pathological changes. Also fructose, produced by a polyol route, can be phosphorylat-ed to fructose-3-phosphate, from which, in turn, 3-deoxyglucosone is synthesized. Each of these compounds is a strong glycosylating agent and can participate in the production of AGE [41]. Glucose is able to have a direct toxic effect on the kidney tissue, resulting in the activation of the protein kinase C enzyme (proteinkinase C, PKC). Hyperglycemia results in an increase in the conversion of glucose through the glycolysis pathway, which in turn increases the synthesis of diacylglycerol (DAG), the key activator of PKC in physiology [42]. As a result of activation of PKC, changes in endothe-lial permeability, expression of vascular endotheli-al growth factor (VEGF) in tissues, and activation and adhesion of leukocytes occur.
The Vascular Endothelial Growth Factor (VEGF) was first isolated in 1983 as a factor contributing to increased vascular permeability in tumors [43, 44]. From the point of view of development of microvascular complications in type 2 diabetes, VEGF-A, which plays a key role in the pathogenesis of microangiopathy, regulates proliferation of vascular endothelial cells in various tissues, including
glomerular capillaries [8, 45]. VEGF-A is a dimeric glycoprotein that acts through the tyrosine kinase receptors VEGFR1 and VEGFR2. These receptors are predominantly found in endothelial cells. With diabetes, excessive activation of VEGF-A occurs. The main source of VEGF-A in the kidneys are podocytes and peritubular epithelial cells, and the receptors are expressed in the glomeru-lar endothelium, pre- and postglomerular vessels. Binding of VEGF to VEGFR2 leads to the proliferation of cells, and the binding of VEGF and VEGFR1, VEGFR2, to an increase in their migration [46].
In addition, directly hyperglycemia can enhance cell proliferation. Increased proliferation and decreased apoptosis of endothelial cells leads to hypertrophy of the renal glomerulus, as well as to the dissociation of the connection between the glomerulus and the collecting duct [8]. In conditions of an increased level of VEGF, the pathological growth of the vessels increases -the formation of glomeruloid bodies or the swelling of tissues. In an intact kidney, VEGF is formed mainly in the area of podocytes and visceral epithelial cells, and binding to the receptor occurs in the region of endothelial cells of the glomeruli. By developing DN, VEGF is found in various cells - endothelial, mesangial, monocytes, macrophages, and under severe renal damage, VEGF is expressed in almost all types of glomerular cells. The binding of VEGF to receptors in the endothelial cell region is most active in the early stages of DN development. As a result of increased proliferation and migration of cells, as well as reduced apop-tosis, the area of the glomerulus increases, which is accompanied by an increase in the glomerular filtration rate. Normally the processes of proliferation and apoptosis are mutually balanced. With diabetes due to the activation of many factors due to hyperglycemia and the development of endo-thelial dysfunction, the equilibrium shifts toward proliferation [8, 20].
An increase in the glomerular filtration rate leads to an increase in the filtration area, respectively, and the filtration factor also increases. In this case, the vascular wall is damaged when intra-cere-bral pressure is increased due to the direct damaging effect of increased pressure on the mesangium and endothelium due to the increased vascular wall tension. Also, the formation of pathological vessels in diabetes mellitus was revealed. Such vessels have a thin wall and a basal membrane, and en-dothelial cells swell. Due to their high permeability, extravasation of plasma proteins from immature vessels takes place. It is this phenomenon that plays the primary role in the development of DN. Due to the increase in blood vessels and their number, kidney glomerular hypertrophy occurs [8].
In the pathogenesis of ND, there is also a transforming growth factor pi (TGF-pi). It was proved that the formation of this cytokine increases in af-
fected kidneys. Various factors, such as hyperglycemia, ATII, KPG, activate the formation of TGF-p1 podocytes. With the stimulation of the receptors, a cascade of reactions is triggered, which ultimately leads to the activation of the caspase enzyme, which entails the destruction of the nuclear material of the podocytes and their subsequent death. TGF-p1 also promotes the expression of a3 (IV) by podocytes, resulting in a thickening of the GBM and developing glomerulosclerosis, and expression in the podocytes of VEGF also increases, which au-tocrine increases its activity and leads to kidney damage [16, 20].
Hyperlipidemia
Hyperlipidemia, characterized by an increase in the total cholesterol, low density lipoprotein (LDL) and very low density lipoprotein (VLDL), lowering the level of high-density lipoprotein (HDL), and also leads to kidney pathology plays a huge role in the development of DN. For a long time this factor was not taken into account, only after studies by J.F. Moorhead and J. Diamond, hy-perlipidemia began to be considered a rather serious nephrotoxic factor [47-49]. Scientists conducted a parallel between the process of formation of ne-phrosclerosis (glomerulosclerosis) and the mechanism of development of vascular arteriosclerosis. This can be fully explained by the structural similarity of the mesangial cells of the glomeruli to the smooth muscle cells of the arteries. Oxidized LDL, growth factors and cytokines increase the synthesis of mesangial matrix components, accelerating the glomerular sclerosis. In turn, lipids filtered into the primary urine can lead to damage to the cells of the renal tubules [34, 50].
There is also a genetic theory of development of DN, which indicates that predisposition plays an important role in both development and progression of kidney pathology [9]. That is, the activity of many damaging mediators, as well as enzymes involved in metabolism, is under genetic control. Thus, the implementation of the damaging effect of one or another factor will depend on the nature of the interaction of the genetically determined activity of this factor and the genetically determined susceptibility to its effect. For example, genes that participate in the development of DN have been identified: genes whose products are involved in the development of hypertension (angiotensino-gen gene (AGT), renin gene (REN), angiotensin converting enzyme I gene (ACE), genes whose products are bound with biochemical damage of renal membranes and the proliferation of mesangium (hepa-ran-sulfate proteoglycan gene, interleukin-1 gene, etc.), genes whose products provide protection against free radical oxidation (catalase gene (SAG), paraoxonase gene (PON), etc.) 47].
In turn, in the progression of DN, there is such a hemodynamic factor as intra-cerebral hyperten-
sion, that is, increased pressure in the capillaries of the renal glomeruli. Of course, in the development of this factor, the renin-angiotensin-aldosterone system (RAAS) plays a major role, namely the high activity of angiotensin II (AT II). This hormone has a significant effect on the process of violation of intrarenal hemodynamics and on the development of structural changes in renal tissue in diabetes [47, 51-52].
The role of the renin-angiotensin-aldosterone system (RAAS) in the development of diabetic ne-phropathy
The mechanisms of operation of the RAAS were discovered in the 20th century in the classical version. Renin - an enzyme which is synthesized in the juxtaglomerular apparatus of kidney, triggers the conversion of angiotensinogen to angiotensin I (AT I), which, in turn, is converted to angiotensin II (AT II) under the action of the angiotensin-con-verting enzyme (ACE). Synthesized AT II has an affinity for two receptor subtypes: AT1 and AT2. But AT II predominantly binds to AT1 receptors, since their expression is more pronounced in an adult than the expression of AT2 receptors. Stimulation of AT1-receptors leads to a pro-inflammatory, proliferative effect. Due to a direct effect on the smooth muscle causes a spasm of arterioles. Also, AT II increases the release of aldosterone by the adrenal cortex, which increases the reabsorption of sodium and water ions. In turn, stimulation of AT2-recep-tors leads to opposite effects.
For a fairly long time, the components of RAAS (prorenin, renin, AT II) were determined only in blood plasma, where their concentration and activity were assessed. But with the course of research in the mid-1980s, it became known about the existence of tissue RAAS, that is, the synthesis of various components of this system in various organs and tissues locally: the heart, kidneys, central nervous system, adipose tissue, pancreas, regardless of circulating system. For example, in various clinical studies, it was noted that diseases such as DN or chronic kidney disease, which are usually accompanied by RAAS hyperactivity, occur with normal or low plasma renin activity (ARP). Paradoxically, at first glance. Diabetes mellitus of type I and type II is characterized by hyporeninemic syndrome. In his studies, Bojestig M. proved that ARP is inversely related to the quality of glycemic control, estimated by the level of glycosylated hemoglobin HbA1c. That is, the worse the glycemic control of diabetes and higher HbA1c, the lower the ARP. In contrast, the level of circulating AT II does not correlate with HbA1c and remains stably high. Just the place of possible formation of AT II are the kidneys. Relatively recently it was proved that the site of synthesis of locally renal AT II is the collective nephron tubes. High concentrations of circulating AT II stimulate the synthesis of renin in the collecting tubes of the kidneys, which in turn promotes
the release of local AT II into the interstitial tissue of the kidneys and into the peritubular capillaries [53]. Also, data on the expression of prorenin receptor podocytes suggesting a direct modulating effect of this component of RAAS on podocytes have recently been obtained [16, 54]. By SD, the activity of locally renal (pro) renin and AT II in collection tubes is increased in conditions of low ARP. This phenomenon can easily be explained by increased activity of AT II, which by feedback mechanism serves as an inhibitor of renal renin synthesis [53]. This "paradox of diabetes" was described by Price D.A. in 1999. In this connection, the increased activity of renal AT II in conditions of diabetes mellitus leads to the activation of AT1-type receptors of ar-terioles, contributing to the spasm of these vessels. Ultimately, intra-cerebral hypertension develops, which, with prolonged action on the glomerular tissue, leads to sclerosis [53, 55].
It is also important to note that stimulation of AT1-type receptors in the tubules and intersti-tium of the kidneys leads to an active synthesis of proinflammatory mediators, cytokines, growth factors that together lead to the development of glomerulosclerosis, tubulointerstitial fibrosis and, consequently, CKD.
Also noteworthy is the fact that in an in vitro study, Y. Huang and co-authors proved that renin itself has a significant stimulating effect on the fibrosis of the renal parenchyma by stimulating the transforming growth factor of TGF-pi mesangial cells, and not related to the mechanism of action of AT II [56-57].
Existing methods of correction of diabetic ne-phropathy and possible perspectives
It is easy to assume that the most effective prevention of development and progression of DN is normalization or ideal compensation of carbohydrate metabolism throughout the course of the disease. A number of diabetological studies (DCCT and UKPDS) have shown that strict glycemic control (HbAlc <7.5%) not only prevents the development of DN in persons who do not suffer from it, but also slows the progression of this complication in patients with UIA and PU. This provision is valid both for patients with type 1 diabetes (the study of DCCT) and for patients with type 2 diabetes (UKPDS study) [47].
Due to the activation of local renal RAAS by CD, it becomes evident that the blockade of local renal AT II activity is a real tool for "protecting the kidney" and preventing the progression of renal failure. And these nephroprotective properties of RAAS inhibitors - ACE inhibitors (ACE inhibitors) and antagonists of AT II receptors (APA) - have an evidentiary basis in large clinical trials with DNP (UKPDS, ADVANCE, MICRO-HOPE, RENAAL, etc.) [53]. Due to these studies, ACEIs were included in the recommendations as first-line drugs for the choice of treat-
ment of diabetic patients in both types of diabetes [53, 58]. But approximately 50% of patients, both with DN and nondiabetic nephropathy, with prolonged use of ACE inhibitors, develop the "escape phenomenon", that is, decrease in antihypertensive and antiproteinuric action of these drugs [53, 59, 60]. At the same time, a high concentration of AT II and aldosterone in the blood plasma is preserved. This phenomenon is explained by the activation of another enzyme, chymase, which stimulates an alternative pathway for the formation of AT II, which is inhibited by the effect of the ACE inhibitor. In this vein, of course, drugs from the APA group have the advantages of inhibiting the binding of AT II to their AT1 receptor, rather than the effect on the amount of AT II formed [53].
But, unfortunayely, the use of both groups of drugs gradually leads to an increase in the activity of renin itself, which activates the entire cascade of angiotensin-converting. Therefore, a huge role was played by the creation of a drug that directly blocks the enzymatic activity of renin itself. This drug is "Aliskiren" ("Rasilez"), it is registered in all countries of Europe, in the USA and since 2007 - in Russia. The high nephroprotective activity of this drug has already been demonstrated in patients with DN in the AVOID study (Aliskireninthe Evaluation of Proteinuria in Diabetes) [53].
Promising drugs are those that are able to inhibit the activity of "mediators" of renal tissue damage: endothelin-1 antagonists and its receptors, cytokine and growth factor blockers, protein ki-nase-C inhibitors, etc. [47].
Also, groups of drugs that normalize lipid metabolism in the body.
Of course, the most progressive way to treat DN can be the method of gene therapy. At present, experimental studies are being carried out on the introduction of gene-modulators of cytokine expression, growth factors, renin and angioten-sinogen into the nuclei of kidney cells, which leads to a weakening of their influence on the kidney tissue and inhibition of the development of glomeru-losclerosis [47].
Conclusion
Summarizing all of the above, we can conclude that the pathogenesis of the development of DN is rather complicated and has a number of its features. This problem has engulfed the whole world and has not lost its relevance at the present time. Treatment of the last stage of DN is not only a complicated process, but also, due to some economic aspects, very costly. It is much easier to deal with the prevention of vascular complications and to try to prevent the transition of the disease to the terminal stage of renal failure, than to treat patients with CKD by hemodialysis. Therefore, despite a detailed study of the existing problem, the issue of correction of nephropathy remains open to this day.
References
1. Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40-50.
2. Dedov I.I., Shestakova M.V., Vikulova O.K. Epidemiology of diabetes mellitus in the Russian Federation: clinical and statistical analysis according to the federal register of diabetes mellitus. Diabetes Mellitus. 2017; 20(1): 13-41.
3. Bondar I.A., Klimontov V.V., Nadev A.P., Rogova I.P. Kidneys in diabetes mellitus: pathomorphology, pathogenesis, early diagnosis, treatment. Novosibirsk: NSTU; 2008.
4. Tomilina N.L. Diabeticheskaya nefropa-tiya. Practical Nephrology. 1998; 1. (In Russ).] URL: http://lekmed.ru/info/arhivy/diabeticheskaya-ne-fropatiya.html. Accessed on 05.05.2018.
5. Rabcin R, Fervenza FC. Renal Hypertrophy and Kidney Disease in Diabetes. Diabetes Me-tab Rev. 1996; (12): 217-241.
6. Kiselnikova O.V. Forecasting and early diagnosis of diabetic nephropathy in children: Dis. ... cand. medical science. Yaroslavl; 2017.
7. Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in Patients with Type 2 Diabetes. N Engl J Med. 2002; 346(15): 11451151.
8. Shishko O.N., Mokhort T.V., Konstanti-nova E.E. The role of endothelial growth factor in blood vessels in the pathogenesis of diabetic ne-phropathy. Medical Journal. 2013. 1(43): 132-135.
9. Smirnov I.E., Kucherenko A.G., Smirnova G.I. Badalyan A.R. Diabetic nephropathy. Russian Pediatric Journal. 2015; 18(4): 43-50.
10. Reutens A.T. Epidemiology of diabetic kidney disease. Med Clin North Am. 2013; 97(1): 1-18. (In Australia.)
11. Dedov 1.1., Kuraeva T.L., Peterkova V.A. Diabetes mellitus in children and adolescents. Moscow: GEOTAR-Media; 2007.
12. Dedov I.I., Shestakova M.V. Diabetes mellitus: diagnosis, treatment, prevention. Moscow: MIA; 2011.
13. Baranov A.A., Namazova-Baranova L.S., Ilyin A.G. Scientific researches in pediatrics: directions, achievements, prospects. Russian Pediatric Journal. 2013; 5: 4-14.
14. Satirapoj B. Nephropathy in diabetes. Adv Exp Med Biol. 2012; (771): 107-122.
15. Shestakova M.V., Chugunova L.A., Sham-khalova M.Sh., Dedov I.I. Diabetic nephropathy: achievements in diagnosis, prevention, treatment. Diabetes Mellitus. 2005; 3: 22-25.
16. Bobkova I.N., Shestakova M.V., Shchukina A.A. Diabetic nephropathy is the focus on damage to podocytes. Nephrology. 2015; 19(2): 33-43.
17. Shankland SJ. Podocyte's response to injury: role in proteinuria and sclerosis. Kidney Int. 2006; 69: 2131-2147.
18. Stitt-Cavanagh E, MacLeod L, Kennedy CRJ. The podocyte in diabetic kidney disease. The Scientific World Journal. 2009; 9: 1127-1139.
19. Reddy GR, Kotlyarevska K, Ransom RF, Menon RK. The podocyte and diabetes mellitus: is the podocyte key to the origins of diabetic nephropathy? Curr Opin Nephrol Hypertens. 2008; 17: 32-36.
20. Wolf G, Chen S, Ziyadeh FN. From the periphery of glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes. 2005; 54(6): 16261634.
21. Ziyadeh FN, Wolf G. Pathogenesis of podo-cytopathy and proteiuria in diabetic glomerulopa-thy. Current Diabetes Reviews. 2008; 4: 39-45.
22. Steffes MW, Schmidt D, Mccrery R, Basgen JM. Glomerular cell number in normal subject and in type 1 diabetic patients. Kidney International. 2001; 59: 2104-2113.
23. Patari A, Forsblom C, Havana M, et al. Nephrinuria in diabetic nephropathy of type 1 diabetes. Diabetes. 2003; 52: 2969-2974.
24. Lewko B, Stepinski J. Hypergliycemia and mechanical stress: Targeting the renal podo-cyte. J Cell Physiol. 2009; 221(2): 288-295.
25. Diez-Sampedro A, Lenz O, Fornoni A. Podocytopathy in diabetes: a metabolic and endocrine disorder. Am J Kidney Dis. 2011; 58(4): 637646.
26. Kriz W, Le Hir M. Pathway to nephron loss starting fromglomerular diseases-insights from animal models. Kidney International. 2005; 67: 404-419.
27. Wiggins RC. The spectrum of podocytopa-thies: a unifying view of glomerular diseases. Kidney Int. 2007; 71: 1205-1214.
28. Vestra MD, Masiero A, Roiter AM, et al. Is podocyte injuryM relevant in diabetic nephropa-thy? Studies in patients with type 2 diabetes. Diabetes. 2003; 52: 1031-1035.
29. Cherney DZ, Scholey JW, Daneman D, et al. Urinary markers of renal inflammation in adolescents with Type 1 diabetes mellitus and normo-albuminuria. Diabet Med. 2012; 29(10): 1297-302.
30. Har R, Scholey JW, Daneman D. et al. The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Diabetolo-gia. 2013; 56(5): 1166-1173.
31. Prunotto M, Ghiggeri G, Bruschi M. et al. Renal fibrosis and proteomics: current knowledge andstill key open questions for proteomic investigation. J Proteomics. 2011; 74(10): 1855-1870.
32. Ponchiardi C, Mauer M, Najafian B. Temporal profile of diabetic nephropathy pathologic changes. Curr Diab Rep. 2013; 13(4): 592-599.
33. Janashia P.Kh., Mirina E.Yu. Variants of correction of lipid metabolism disorders in patients with type 2 diabetes mellitus. Russian Medical Journal. 2008; 16(11): 1561-1566.
34. Zakharyina O.A., Tarasov A.A., Babaeva A.R. Actual aspects of drug prevention and treatment of diabetic angiopathy. Lekarstvenny Vestnik. 2012; 5(45): 14-22.
35. Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Me-tab. 2009; 94(9): 3171-3182.
36. Kacso IM, Kacso G. Endothelial cell-selective adhesion molecule in diabetic nephropathy. Eur J Clin Invest. 2012; 42(11): 1227-1234.
37. Eleftheriadis T, Antoniadi G, Pissas G, et al. The renal endothelium in diabetic nephropathy. Ren Fail. 2013; 35(4): 592-599.
38. Keech A, Simes RJ, Barter P, et al. FIELD study investigators. Effects of long-term fenofi-brate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005; 366(9500): 1849-1861.
39. Gabbay KH. Hyperglycemia, polyol metabolism, and complications of diabetes mellitus. Annual Review of Medicine. 1995; 26: 521-536.
40. Kinoshita JH. A thirty year journey in the polyol pathway. Exp Eye Res. 1990; 50(6): 567-573.
41. Gabbay KH. The sorbitol pathway and the complications of diabetes. The New England Journal of Medicine. 1973; 288(16): 831-836.
42. Zavodnik I.B., Dremza I.K., Lapshina E.A. Cheshchevik V.T. Diabetes mellitus: metabolic effects and oxidative stress. Biological membranes. 2011; 28(2): 83-94.
43. Senger DR, Galli SJ, Dvorak AM. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983; 219: 983-985.
44. Smirnova O.M., Kuzmin A.G., Lipatov D.V., Shestakova M.V. Perspectives of DR treatment: effect on the growth factor of the endothe-lium (literature review). Diabetes Mellitus. 2009; 2: 33-38.
45. Aiello LP, Wong JS. Role of vascular endo-thelial growth factor in diabetic vascular complications. Kidney Int Suppl. 2000; 58(77): 113-119.
46. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascularendothelial growth (VEGF) and its receptors. The FASEB Journal. 1999; 13: 1018.
47. Shestakova M.V. Diabetic nephropa-thy: the results of the XX century, the prospects of the XXI century. Diabetes Mellitus. 2000; 1: 15-18.
48. Moorhead JF. Lipids and the pathogenesis of kidney disease. Am J Kidney Dis. 1991; 27 (1): 6570.
49. Diamond J. Focal and segmental glomeru-losclerosis: analogies to atherosclerosis. Kidney Int. 1988; 33: 917-924.
50. Dedov I.I., Shestakova M.V. Algorithms of specialized medical care for patients with diabetes mellitus. Moscow: Endocrinology Research Center; 2007.
51. Anderson S, Jung FF, Ingelfinger JR. Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. Am J Physiol. 1993; 265: 477-486.
52. Wolf G. Molecular mechanisms of angioten-sin II in the kidney: an emerging role in the progression of renal disease: beyond haemodynamics. Nephrol Dial Transplant. 1998; 13: 1131-1142.
53. Shestakova M.V. The role of tissue renin-an-giotensin-aldosterone system in the development of metabolic syndrome, diabetes mellitus and its vascular complications. Diabetes Mellitus. 2010; 3: 14-19.
54. Ichihara A, Kaneshiro Y, Takemuro T. et al. The (pro) renin receptor and the kidney. Semin Nephrol. 2007; 27: 524-528.
55. Price DA, Porter LE, Gordon M. The Paradox of the Low-Renin State in Diabetic Nephropa-thy. J Am Soc Nephrol. 1999; 10: 2382-2391.
56. Karabaeva A.Zh., Kayukov I.G., Yesayan A.M., Smirnov A.V. Renin-angiotensin-aldosterone system in chronic kidney disease. Nephrology. 2006; 10 (4): 43-48.
57. Huang Y, Wongamorntham S, Kasting J, et al. Reninin creases mesangial cell transforming growth factor-beta1 andmatrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 2006; 69 (1): 105-113.
58. Severina A.S., Shestakova M.V. New on the mechanisms of development, diagnosis and treatment of diabetic nephropathy. Diabetes Mellitus. 2001; 3: 59-60.
59. Shiigai T, Shichiri M. Late escape from the antiproteinuric effect of ACE inhibitors in non-diabetic renal disease. Am J Kidney Dis. 2001; 37: 477-483.
60. Shamkhalova M.Sh., Trubitsyna N.P., Shestakova M.V. The phenomenon of partial evasion of the blockade of angiotensin AT II in patients with type 2 diabetes and diabetic nephropathy.
Therapeutic archive. 2008; 1: 49-52.
Contacts
Corresponding author: Zharikov Aleksandr Yur-yevich, Doctor of Biological Sciences, Associate Professor, Head of the Department of Pharmacology of ASMU, Barnaul. 656056, Barnaul, ul. Papanintsev, 126. Tel.: (3852) 241859. E-mail: [email protected]
Shchekochikhina Rita Olegovna, graduate student of the Altai State Medical University, Barnaul. 656038, Barnaul, Lenina Prospekt, 40. Tel.: (3852) 566869. Email: [email protected]
