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Darenskaya, M.; Kolesnikov, S.; Semenova, N.; Kolesnikova, L. Significance of Determining Oxidative Stress in Diabetic Nephropathy. Encyclopedia. Available online: https://encyclopedia.pub/entry/47939 (accessed on 21 June 2024).
Darenskaya M, Kolesnikov S, Semenova N, Kolesnikova L. Significance of Determining Oxidative Stress in Diabetic Nephropathy. Encyclopedia. Available at: https://encyclopedia.pub/entry/47939. Accessed June 21, 2024.
Darenskaya, Marina, Sergey Kolesnikov, Natalya Semenova, Lyubov Kolesnikova. "Significance of Determining Oxidative Stress in Diabetic Nephropathy" Encyclopedia, https://encyclopedia.pub/entry/47939 (accessed June 21, 2024).
Darenskaya, M., Kolesnikov, S., Semenova, N., & Kolesnikova, L. (2023, August 11). Significance of Determining Oxidative Stress in Diabetic Nephropathy. In Encyclopedia. https://encyclopedia.pub/entry/47939
Darenskaya, Marina, et al. "Significance of Determining Oxidative Stress in Diabetic Nephropathy." Encyclopedia. Web. 11 August, 2023.
Significance of Determining Oxidative Stress in Diabetic Nephropathy
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Diabetes mellitus (DM) belongs to the category of socially significant diseases with epidemic rates of increases in prevalence. Diabetic nephropathy (DN) is a specific kind of kidney damage that occurs in 40% of patients with DM and is considered a serious complication of DM. Hyperglycemia has a negative effect on renal structures due to a number of factors, including the activation of the polyol and hexosamine glucose metabolism pathways, the activation of the renin–angiotensin–aldosterone and sympathetic nervous systems, the accumulation of advanced glycation end products and increases in the insulin resistance and endothelial dysfunction of tissues. The above mechanisms cause the development of oxidative stress (OS) reactions and mitochondrial dysfunction, which in turn contribute to the development and progression of DN. Modern antioxidant therapies for DN involve various phytochemicals (food antioxidants, resveratrol, curcumin, alpha-lipoic acid preparations, etc.), which are widely used not only for the treatment of diabetes but also other systemic diseases. 

diabetes mellitus diabetic nephropathy oxidative stress biomarkers antioxidant therapies vitamins

1. Introduction

Diabetes mellitus (DM) belongs to the category of socially significant, non-infectious diseases with epidemic rates of prevalence. According to the International Diabetes Federation (IDF), 537 million people currently suffer from diabetes—a number that is expected to increase by more than 50% to 784 million by 2045 [1]. Disease prognosis is usually extremely unfavorable and, unfortunately, this trend has been maintained for many years [2]. Despite successes in studying the mechanisms of DM development and impressive results in the development of new drugs for the control of glycemia, the problems associated with DM are still increasing [3]. There are social and economic burdens that are determined by the development of micro- and macro-vascular complications, which are the causes of early disability and mortality of patients [4]. Clinical DM complications are mainly represented by stroke, coronary heart disease, peripheral artery disease, retinopathy, neuropathy and nephropathy [5].

2. Diabetic Nephropathy (DN): Pathogenesis and Existing Correction Methods

DN is a specific kind of kidney damage that occurs in 40% of patients with DM, according to recent data [6]. Chronic renal failure (CRF) due to DN significantly contributes to the mortality rate of patients with DM and is one of the main causes of mortality in patients with type 1 DM (T1DM) [7]. In patients with type 2 DM (T2DM), DN ranks third among the causes of death after cardiovascular diseases and oncological pathologies [8].
DN combines a number of changes in various renal structures (arteries, arterioles, kidney glomeruli and tubules) with the development of glomerular hypertension, often leading to the development of diffuse or nodular glomerulosclerosis and, subsequently, CRF [9]. A number of structural and functional events consistently occur in the kidney tissues of patients with DN. It is classically distinguished into several consequent stages: albuminuria, proteinuria with preserved kidney function and the progressive decrease in the functional activity of the kidneys until the terminal stage [10]. Currently, DN is not considered to be a fatal complication of DM since its development can be prevented.
Additionally, the possibility of the early preclinical diagnosis of DN has significantly expanded. Until recently, albuminuria was considered a key factor in glomerular damage (i.e., “albuminuria was a centric” model of pathogenesis) [9][11]. However, morphological studies have shown that the characteristic changes in kidney tissues are already present under the conditions of normal albumin excretion and that the detection of albuminuria indicates the presence of sclerosis in 20–25% of nephrons [12][13].
A key pathogenetic factor in DN development is persistent hyperglycemia [14]. Along with possible genetic predisposition (i.e., a smaller than usual number of nephrons in the kidneys, etc.), stable hyperglycemia is the basis for the formation of several complex and not yet fully understood pathological mechanisms that damage various renal structures (i.e., mesangial, tubular, interstitial and vascular structures) [10]. These effects are enhanced in the presence of various vascular risk factors (obesity, smoking, metabolic syndrome, etc.) [15]. Together, the impact of these factors is the formation of glomerular hyperfiltration (at the initial stage) and glomerular hypertension. Subsequently, the mechanism for autoregulating the renal tubular arteriole tone is disrupted due to systemic arterial pressure, directly affecting intraglomerular pressure, and glomerular hypertension develops from transient to constant [16]. The emergence of podocyte (glomerular epithelial cell) disorders and the development of podocytopathy are important factors in the development of albuminuria. Albuminuria, in turn, is considered an important mechanism for the further progression of glomerular damage, the formation of nodular glomerulosclerosis, the increase in the mesangial matrix, glomerular hyalinosis and tubulo-interstitial fibrosis [12][14].
Hyperglycemia has a negative effect on renal structures due to several factors, including the accumulation of advanced glycation end products (AGEs), the activation of the polyol and hexosamine glucose metabolism pathways, increased oxidative stress (OS) reactions, the activation of the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system and the increased insulin resistance and endothelial dysfunction of tissues [7][14].
It is unequivocally recognized that all the above mechanisms cause the development of OS reactions and mitochondrial dysfunction, which contribute to DN development and progression [17].
The main principle of DN prevention and treatment is the correction of metabolic and hemodynamic disorders, particularly the maintenance of good glycemic control (glycated hemoglobin (HbA1c) < 7%), the normalization of systemic blood pressure (<130/80 mm Hg), a reduction in intraglomerular hypertension and the elimination of dyslipidemia [9][10][13][14]. In this regard, HbA1c-lowering drugs, insulinotropic drugs, insulin-sensitizing drugs, anorectic drugs, incretin hormone mimic drugs, lipid-lowering drugs, drugs that prevent glucose reabsorption in the kidneys, etc., have become important [9][13][14][16]. RAAS blockers, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, remain the standard drugs approved for DN, according to international treatment algorithms [13][14]. Their nephroprotective properties have been evidenced in large clinical trials for the treatment of DN [9]. As a result, ACE inhibitors are recommended as the first-line treatment for DN in both types of diabetes [9][16]. At the same time, new classes of nephroprotective drugs are being developed that interrupt the chain of pathological changes in the kidneys caused by hyperglycemia or other factors (e.g., protein kinase C (PKC) inhibitors, cytokine and growth factor blockers, endothelin-1 antagonists, etc.) [9][13][14][16][18].

3. OS

During cell metabolism, free radicals (FRs) (otherwise known as reactive oxygen species (ROS) or reactive nitrogen species (RNS)) are continuously formed [19]. They can be of two types: some are the normal metabolic products of endothelial cells, which are caused by the release of super-oxides via phagocyte and nitric oxide (NO) activation, while others occur under altered environmental conditions (e.g., FRs in water and organic molecules that are synthesized under the action of ultraviolet, ionizing radiation, toxic substance or pathological conditions) [19][20][21]. FRs are highly reactive particles that contain unpaired electrons; that is, one or more electrons are missing in the outer orbital [22]. The main suppliers of FRs are mitochondria (mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)) [23]. Superoxide radical (O2) plays an initiating role in this process, since after formation in mitochondria, it can turn into more reactive forms, such as hydroxyl (OH), hydroperoxyl and peroxyl (ROO) radicals, hydrogen peroxide, singlet oxygen (1O2), nitric oxide radicals (NO), nitrogen dioxide radicals (NO2), etc. [19]. In low and moderate concentrations, ROS act as important elements in the cellular links of the immune system by regulating the synthesis of prostaglandins, leukotrienes and thromboxanes, as well as participating in the destruction of xenobiotic molecules, the renewal and modification of cellular biomembranes, the regulation of apoptosis, etc. [24].
Under pathological conditions, the balance of ROS production and detoxification by the antioxidant defense system (AOD) is disturbed, which leads to system imbalance and OS development [20][21][22]. Sies provided the following definition of OS: “a violation of the balance between pro-oxidants and antioxidants towards the predominance of pro-oxidants, which leads to a violation of redox signaling and redox control and/or damage to molecules” [19]. The excessive production of ROS causes the oxidation of macromolecules (i.e., lipids, proteins and deoxyribonucleic acid (DNA)), which ultimately leads to modifications and changes that can persist for a long time [25]

4. DN: The Significance of Determining OS

The kidneys are the second organ after the heart in terms of the number of mitochondria, which provide the best conditions for the synthesis of adenosine triphosphate (ATP) and the absorption of ultrafiltrate and dissolved substances [26]. The functions of renal structures depend on fatty acid β-oxidation and mitochondrial oxidative phosphorylation, during which a large number of ROS are formed [27]. Thus, the balance between the production of mitochondrial ROS and their neutralization via the AOD system is crucial for the normal function of mitochondria in the kidneys [28]. Most studies have claimed that mitochondrial dysfunction and the development of OS are the main pathogenetic factors responsible for the initiation and progression of DN [3][29]. At the same time, mitochondrial dysfunction is characteristic of various cells in renal structures, including endothelial cells and podocytes [30][31]. OS can mediate podocyte cell death, especially podocyte apoptosis, via many signaling pathways, as well as cell cycle arrest [32]. When certain pathways, such as PI3K/Akt, transforming growth factor β1 (TGF-β1)/p38-mitogen-activated protein kinases (p38-MAPK) and nuclear factor kappa B (NF-kB), are activated, this induces endothelial cell apoptosis, inflammation, autophagy and fibrosis, which cause histological and functional kidney disorders and, ultimately, kidney damage [33].
Hyperglycemia triggers a cascade of biochemical transformations, leading to damage to vascular walls and primarily activating the formation of super-toxic ROS molecules in mitochondria [14]. Inside the mitochondria, these reactive elements damage respiratory chain enzymes and mitochondrial DNA. Going beyond the mitochondria, reactive radicals trigger other mechanisms that are associated with the toxic effects of hyperglycemia, including vascular endothelial dysfunction, the formation of AGEs, the activation of PKC and NF-kB, epigenetic changes, etc. [34]. Despite that FRs live for less than a minute, proteins, fats and nucleic acids that have been damaged by them exist for a long time. AGEs also have a damaging effect on renal structures and their accumulation underlies the mechanism of “metabolic memory”, which is when modifications to biomolecules caused by ROS can lead to deviations in cellular function a considerable time after the initial manifestation of DM [35]. As a result, it becomes important to achieve good glycemic control within the first months of the occurrence of the disease. The spectrum of pathological effects of AGEs is extremely large. 

5. DN and OS: Experimental Studies

The administration of multiple consecutive injections of STZ is widely used to induce experimental models of DN as it selectively destroys beta cells in the pancreas, which leads to a decrease in insulin secretion [36]. In addition to its cytotoxic effect, STZ also contributes to the development of OS and mitochondrial dysfunction and the suppression of the activity of enzymes that destroy ROS. Thus, in rats with STZ-induced DM, changes in mitochondrial bioenergetics have been shown to precede the development of albuminuria and histological changes in the kidneys [37]. Mitochondrial fragmentation and decreases in ATP content have been observed in proximal tubule cells in the early stages (first four weeks) of DM in the absence of albuminuria and specific glomerular pathologies [38]. The progression of DM indicates mitochondrial dissociation, OS generation and glomerular changes [39]. The mitochondrial biosynthesis of ROS mediated by proliferator-activated receptor-γ coactivator 1-alfa (PGC-1α) coactivators and NRF1 and TFAM transcription factors may be key in maintaining mitochondrial function [37][40]. Mitochondrial abnormalities, such as defective mitophagy, the formation of mitochondrial ROS and decreased mitochondrial membrane potential, have been reported in the glomeruli of db/db mice (which are used as models of obesity, DM and dyslipidemia), which were accompanied by a decrease in PINK expression and increased apoptosis [38][41].
Endothelial NO synthases decrease, leading to the increased production of ROS and OS, which is associated with DN progression in experimental animal models [41]. In rats with DN, significant increases in glucose, blood urea nitrogen (BUN), N-acetyl-β-D-glucosaminidase and proteinuria levels have been found, along with concomitant decreases in the glomerular filtration rate (GFR), elevated levels of 8-OHdG, TGF-β1, MDA and GSH and reduced levels of GR and SOD [42]. Histological examinations have also revealed significant changes, including glomerulosclerosis and interstitial fibrosis, in diabetic groups [43]. Diabetic rats with STZ-induced DM have demonstrated hyperglycemia, which was closely associated with marked increases in MDA and protein carbonyl content, decreases in GSH, SOD and CAT levels in the kidneys and high levels of blood creatinine, BUN and urine albumin [44]. In addition, the increased expression of p65 NF-kB and proinflammatory cytokines (e.g., TNF-α, interleukin 1β (IL-1β) and IL-6) has been noted in the renal tissues of animal models [44]. Db/db mice have been shown to develop more kidney damage associated with molecular-1 and neutrophilic gelatinase lipocalin in the kidneys and urine, along with folds and disorders in renal tubule basement membranes, the accelerated formation of ROS, NOX and MDA and decreases in SOD, CAT and GPx levels [45]. The incubation of glyoxal (a byproduct of glucose autooxidation, involved in protein/lipid glycation and AGEs and LPO product formation) has been reported to reduce rat renal cell viability and lead to membrane lysis, the formation of ROS and LPO, mitochondrial membrane potential collapse and lysosomal membrane leakage [46]. AGEs have a toxic effect that contributes to the formation of DN via their accumulation in the vessels and various structures of the kidneys (i.e., mesangium, endothelium, podocytes, etc.). Experiments have shown that podocytes are the main target of AGEs, as evidenced by their expression of RAGE receptors [40]

6. DN and OS: Clinical Studies

In numerous clinical studies on DN development, the significant activation of OS reactions is in the form of increases in the serum levels of TBARs, MDA, AGEs, protein carbonyls and AOPP, as well as increases in urine 8-OHdG levels [29][47][48][49][50]. In patients with DM, a large number of oxidants are formed by non-functioning mitochondria and NOX1 in the liver [51].
A special pathogenetic role in DN is likely played by a set of negative factors that have damaging effects on renal tubules. Thus, it has been shown that increased OS, in combination with inflammation, cellular apoptosis and tissue fibrosis, leads to the steady progressive loss of kidney function and alters the glomerular filtration barrier [52]. The development of microalbuminuria is associated with insufficient glycemic control, hyperlipidemia, OS and the accumulation of AGEs [53]. In DN, the excessive accumulation of lipids in podocytes has been described, which leads to mitochondrial OS lipotoxicity, inflammatory reactions, actin cytoskeleton remodeling, insulin resistance (IR) and endoplasmic reticulum (ER) stress [40].
The hyperproduction of ROS leads to a consistent increase in TGF-β1, which contributes to the development of fibrosis in the tubulointerstitial parts of the kidneys [54]. In patients with DN, significant increases in glucose levels, carbonyl groups and ceruloplasmin, CAT and thiol levels have been reported [55]. Recently, the importance of the determination of LPO, VEGF primary products, podocyte damage markers and immuno-inflammatory factors in DN patients has been indicated [56].
Elevated values of the carbonyl stress indicator MGO have also been observed in the studies [57]. 8-OHdG is a modified nucleoside base that is the product of oxidative DNA damage, which is formed by cutting oxidized guanosine from mitochondrial and nuclear DNA [19]. It has been found that the average level of 8-OHdG in the urine of patients with T1DM is significantly higher, especially in patients with persistent or intermittent microalbuminuria [58]. Data on the correlation between 8-OHdG and leukocyte content in urine and the severity of DN development are of particular interest, which confirms the importance of using these markers for predicting DN development and progression in patients with DM [59]. Increased values of this parameter have been observed in patients in the initial stages of DN, along with reduced values of telomere length [60]
Statistically significant decreases in vitamin A, vitamin C and vitamin E concentrations with simultaneous increases in fasting blood sugar, postprandial blood sugar, blood urea, serum creatinine, HbA1c, sialic acid and microalbumin levels have been documented in the urine of patients with DN [61]. In patients with T2DM, DN and concomitant obesity, α-tocopherol and β-carotene levels in blood serum have been found to be below the optimal level, along with the significantly reduced urinary excretion of vitamins B1 and B2 and high vitamin D deficiency [62]. The same authors also found negative correlations between the ratio of vitamin C and E concentrations, glucosuria and postprandial glycemia, which indicated the need to maintain optimal levels of these vitamins [63]

7. Opportunities for Antioxidant Therapies

The timely and dosed use of effective antioxidant agents is of particular importance in the treatment of diseases that have OS as their pathophysiological and pathobiochemical basis and is also necessary for the correction of pro-oxidant and antioxidant systems and oxidative metabolism in general. While in vitro studies have demonstrated the metabolic effects of antioxidant supplements, particularly with regard to the biology and activity of insulin [64], clinical studies are far from establishing the exact mechanisms of their action [65]. Modern antioxidant therapies for DN include various phytochemicals (food antioxidants, resveratrol, curcumin, preparations of α-LC, α-tocopherol, vitamin C, selenium, etc.), which are widely used not only for the treatment of DM but also other systemic diseases [66]. It has also been suggested that therapeutic approaches that target the exact source of renal ROS in DN may have certain advantages in terms of nephroprotection from OS [29].

8. Conclusions

T1DM and T2DM and their complications constitute serious public health problems worldwide and have high morbidity and mortality rates. DN is considered one of the serious complications and combines changes in various renal structures with the development of glomerular hypertension, often leading to the development of diffuse or nodular glomerulosclerosis and, subsequently, CRF. Most modern methods for treatments aimed at slowing down the progression of DN have side effects and do not produce unambiguous positive results in the long term. In most experimental and clinical studies, it has been claimed that OS and mitochondrial dysfunction are the main pathogenetic factors that are responsible for the initiation and progression of DN and that the balance between the production of mitochondrial ROS and their neutralization via the AOD system is crucial for the proper functioning of kidney mitochondria. Modern antioxidant therapies for DN include various substances (e.g., fat- and water-soluble vitamins, resveratrol, curcumin and α-lipoic acid preparations), which are widely used for the treatment of not only diabetes but also other systemic diseases. It has also been suggested that therapeutic approaches that target the source of ROS in DN may have certain advantages in terms of nephroprotection. Promising therapeutic options for the treatment of diseases caused by OS include mitochondrial-targeted antioxidants, which can be delivered to mitochondria in vivo via different administration methods. Thus, the measurement of OS biomarkers and AOD components may have advantages in terms of early diagnosis and intervention and deserves to be considered as an additional analysis tool. It is also important to develop individual approaches for treating patients with DN using therapeutic antioxidant agents.

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