Antioxidants used in Streptozotocin Induced Diabetic Nephropathy:

A Concise Review

Kajal Pansare¹*, Ganesh Sonawane², Yogesh Ahire³, Vinod Bairagi⁴

¹Research Scholar, Department of Pharmacology,

KBHSS Trusts, Institute of Pharmacy, Malegaon, Nashik - 423203.

²Assistant Professor, Department of Pharmaceutical Chemistry,

Divine College of Pharmacy, Satana, Nashik - 4233201.

³Assistant Professor, Department of Pharmacology,

KBHSS Trusts, Institute of Pharmacy, Malegaon, Nashik - 423203.

⁴Professor, Department of Pharmacology,

KBHSS Trusts, Institute of Pharmacy, Malegaon, Nashik - 423203.

*Corresponding Author E-mail: kajalgsonawane@gmail.com

ABSTRACT:

Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal failure throughout much of the world. The synthetic drugs are effective in controlling the blood sugar but with many other complications. To overcome this, the need for natural antioxidants, this may be used as a dietary supplement to prevent diabetic nephropathy. Most drugs found to cause nephrotoxicity which exerts toxic effects by one or more common pathogenic mechanisms. Among them, Streptozotocin is the most frequently used drug to induced diabetic nephropathy in rodents offers relevant models to study the effect of antioxidants. The model has so far been used by many researchers to study the effect of drugs in diabetes. In this review, we compiled several antioxidants that are used in the management of Streptozotocin induced diabetic nephropathy with their parameters evaluated.

KEYWORDS: Diabetes, Diabetic nephropathy, Hyperglycaemia, Streptozotocin, Nephrotoxicity.

INTRODUCTION:

Diabetic nephropathy (DN) is clinically defined as the progressive development of renal insufficiency in the setting of chronic hyperglycemia. The functional disorders in DN are manifested by early microalbuminuria, renal hyperfiltration, hyper-perfusion, and increased capillary permeability to macromolecules and proteinuria with or without chronic renal insufficiency that leads to end-stage renal disease (ESRD)¹.

Nephropathy is reported to develop in 30-40% of patients with diabetes1 and has become a major cause for ESRD². In diabetes, the toxic concentration of blood glucose levels damages the renal tissue, which leads to altered renal function, causing diabetic nephropathy. Elevated blood glucose and glycosylated protein levels, associated with increased oxidative stress produce hemodynamic changes within the renal tissue, thereby leading to altered kidney function in patients with diabetes mellitus³.

Approximately, 30% of all diabetic patients convert into diabetic nephropathy after 10-20 years of diabetes. One of the primary targets of hyperglycemia is tubular cells of the kidney and chronic exposure of high blood glucose level contributes early renal pathological alterations in the form of tubulointerstitial changes, increase in tubular basement membrane thickening that further characterized by glomerular and tubular hypertrophy, accumulation of protein matrix and development of renal hypertrophy⁴. Elevated glucose and cholesterol levels, increased production of inflammatory cytokines are the predisposing factors for the progression of renal damage in diabetic nephropathy⁵. Nephropathy is one of the major complications of both type 1 and type 2 diabetes mellitus, and the morbidity and mortality due to diabetic nephropathy continue to increase in industrialized nations. Recently, several medicinal herbs or natural products have been highlighted as an alternative to the current management of DN⁶. In DN, when hyperglycemia is maintained for a long time, nephropathy occurs due to the multiple cellular mechanisms including, activation of protein kinase C (PKC) pathway, cytokines production, and enhanced polyol pathway, increased formation of advanced glycation end products (AGE), increased oxidative stress and hexosamine pathway. It can lead to high production of reactive oxygen species (ROS) and a simultaneous reduction of the antioxidant defense mechanisms, which can cause oxidative stress⁷. Hyperglycemia in diabetes leads to mitochondrial dysfunction and increases the reactive free radicals; then causes DNA damage, which results in apoptotic cell death. Hyperglycemia also causes oxidative stress, increases glutathione (GSH) oxidation and lipid peroxidation. Finally, hyperglycemia induces oxidative stress in diabetic nephrons and results in activation of multiple biochemical pathways that lead to renal cell death, increased albuminuria, and renal dysfunction⁸. In recent years, diabetic nephropathy was defined by the evidence of a renal disturbance which is characterized by the presence of proteinuria, equal or more than 300mg/day, in a diabetic patient. All these new findings lead to a change in diabetic nephropathy concept, to the new one “diabetic kidney disease” (DKD)⁹. Because DN is the major cause of chronic kidney disease (CKD), which normally leads to ESRD or dialysis. The mortality of dialysis patients with DN is higher than that of non-diabetic patient¹⁰. If glucose level in the blood remains high (hyperglycaemia) over a long period, this can result in continuing damage to organs, such as the kidneys, liver, eyes, nerves, heart, and blood arteries. People with diabetes are in a risk of other complications associated with damaged tissue of vital organs that may lead to death¹¹. Many studies on experimental animals and diabetic patients have confirmed that hyperglycemia resulted in the progress of nephropathy⁸. Untreated cases of diabetes show severe tissue and vascular damages leading to serious complications such as retinopathy, neuropathy, nephropathy, cardiovascular complications, and ulceration¹².

Diabetogenic Chemical Model to Induced Diabetic Nephropathy:

Streptozotocine model has been useful for the study of multiple aspects of the disease. The dose of these agents required for inducing diabetes depends on the animal species, route of administration, and nutritional status¹³.

Streptozotocin-Induced Diabetic Nephropathy

Streptozotocin (STZ) is a naturally occurring nitrosourea with a molecular weight of 265 and empirical formula of C₁₄H₂₇N₅O₁₂. It is widely used to induce insulin-dependent diabetes mellitus in experimental animals because of its toxic effects on islet beta cells¹⁴. Streptozocin (STZ) is a glucosamine-nitrosourea compound that has been in the clinical trial since 1967¹⁵. STZ has four important biological properties as evidenced by its antibiotic, β-cell cytotoxic, oncolytic, as well as oncogenic effects. STZ is an antibiotic and antitumor agent, which induces diabetes mellitus via the reduction of nicotinamide adenine dinucleotide in pancreatic β-cells in vivo¹⁶. Diabetes can be induced by STZ either by a single injection or by multiple low dose injection of STZ. It is the most commonly used drug for the induction of diabetes in rats¹⁵. Diabetes was induced in male Wistar albino rats aged 2–3 months (180–200 g/body weight) by intraperitoneal administration of STZ dissolved in freshly prepared 0.01M citrate buffer, pH 4.5. After 72h, rats with marked hyperglycemia (fasting blood glucose≥250mg/dl) were selected and used for the study¹⁷. Further, the administration of a 5% glucose solution during the first 24h following STZ injection prevented early mortalities¹⁸. The fasting serum glucose level was measured by the glucose oxidase-peroxidase method using a glucose test kit. Only rats with fasting blood glucose level of 250mg/dl and above were considered as diabetic and those with blood sugar level 130mg/dl and below were considered as non-diabetic¹⁹. The main characteristic symptoms in STZ-induced diabetic rats showed a significant increase in blood glucose (hyperglycemia), water intake (polydipsia), food intake (hyperphagia), which accompanied with severe loss of body weight. Increased water and food consumption result in a direct accumulation of glucose in the blood and an increase in the urinary excretion of glucose²⁰. STZ-induced diabetic rats, severe hyperglycemia were developed, with a marked increase in proteinuria and albuminuria¹⁹.

Mechanism of Streptozotocin Induced Diabetic Nephropathy:

Streptozotocin is a naturally occurring chemical; accustomed to produce Type- 1 diabetes within animal design and Type- 2 diabetes along with multiple low doses. Streptozotocin prevents insulin release and causes a situation of insulin-dependent diabetes mellitus. Streptozotocin is less lipophilic as well as selectively gathered in pancreatic beta tissue via the actual low-affinity GLUT2 sugar transporter within the plasma membrane²¹. Thus, insulin-producing cells that do not express this glucose transporter are resistant to streptozotocin²². The streptozotocin enters the pancreatic cell via a glucose transporter-GLUT2 (Glucose transporter 2) and causes alkylation of DNA. Further STZ induces activation of poly adenosine diphosphate ribosylation and nitric oxide release, as a result of STZ action, pancreatic -cells are destroyed by necrosis and finally induced insulin-dependent diabetes²³. Streptozotocin is also selective for the pancreatic islet beta-cell and can also produce permanent diabetes in mice, rats, dogs, and other species although the rabbit is relatively resistant²⁴.

Intravenous injection of 60mg/kg dose of streptozotocin in adult Wistar rat’s causes swelling of pancreas followed by degeneration of Langerhans islet beta cells and induces experimental diabetes mellitus in the 2-4 days. Three days after the degeneration of beta cells, diabetes was induced in allanimals¹⁵. Streptozocin is a natural diabetogenic agent that induces permanent diabetes in animal models by damaging pancreatic β-cells that stops insulin production. Its β-cell toxicity is reasoned through the Carbamoylation of proteins, alkylation of DNA, the release of free radicals (ROS and RNS), and inhibition of O-GlcNAcse31. The biochemical Streptozotocin enters the pancreatic cell via a glucose transporter-GLUT2 and causes alkylation acid (DNA)²⁵. Streptozotocin prevents cellular reproduction with a much smaller dose than the dose needed for inhibiting the substrate connected to the DNA or inhibiting many of the enzymes involved in DNA synthesis¹⁴.

Antioxidants used in Streptozotocin Induced Diabetic Nephropathy:

There is considerable evidence that induction of oxidative stress is a key process in the onset of diabetic complications. The precise mechanisms by which oxidative stress may accelerate the development of complications in diabetes are only partly known. Evidence for the protective effect of antioxidants has been presented in experimental, clinical, and epidemiological studies, which have demonstrated that antioxidants might be helpful in treating diabetes and its complications. Several animal studies on antioxidants as protective agents have been conducted. The most important studies have been performed utilising antioxidants in experimental diabetic models. Some of antioxidants used in Diabetic Nephropathy with their observable biomarkers are listed in Table 1.

Table 1. List of some antioxidants used in Diabetic Nephropathy

Sr. No.	Name of Antioxidant	Parameters Protected	References
1	Zamzam water	HR and BP, Glucose level, Insulin immunoassay, Kidney function tests, Oxidative stress biomarkers, Histopathology and immunohistochemistry study, Islet cell extraction and treatment	Maleky et., al. 2021
2	Probucol	Blood glucose; BW, body weight; KW, kidney weight of right kidney; Scr, serum creatinine; BUN, blood urea nitrogen; TC, total cholesterol; TG, triglyceride, renal tubular injury, oxidative injury and apoptosis	Yang et., al. 2017
3	Co-Enzyme Q10 and N-Acetylcysteine	Body weight, kidney weight, Blood Glucose level, Total Protein, Albumin, Creatinine, Creatinine clearance, BUN and uric acid, urine volume, urinary protein and albumin excretion, anti-oxidant markers, myeloperoxidase (MPO) activity and NO, histopathology	Mahajan et., al 2020
4	Luteolin	Biochemical Analyses, Antioxidant Measurement, Histology, Heme Oxygenase-1 and Phosphorylated Akt.	Wang et., al 2011
5	Moutan Cortex	Blood glucose, serumcreatinine, and urine protein, SOD, glutathione peroxidase and catalase, MDA, Immunohistochemical assay	Zhang et., al 2014
6	Pioglitazone	Biochemical Measurements, Antioxidants and Inflammatory Markers, histopathology.	Karabas et., al 2013
7	Thymoquinone	Biochemical Tests, Histopathological Study, Immunohistochemical Study	Omran, et., al. 2014
8	Ethyl Vanillin	blood urea nitrogen (BUN) and serum creatinine (SCr), Histological Observation and TUNEL Staining, Immunohistochemical Staining, Lipid Peroxidation Assay, Determination of the Antioxidant Enzyme Activity, Cell Culture, Cell Cytotoxicity Assay, Cell Apoptosis and TUNEL Assay, Intracellular Reactive Oxygen Species Analysis, Antioxidant System Assay, Western Blotting.	Tong et., al. 2019
9	Kaempferol	Measurements in the plasma, serum, and urine, Measurements in the kidney homogenate, Western blotting analysis, Histological evaluation	Alshehri et., al. 2021
10	Hesperidin	Serum urea and creatinine analysis, Biochemical analysis, Glutathione level, MDA level, TGF-b1 and 8-OHdG levels, Histopathological analysis, Immunohistochemical analysis	Kandemir et., al, 2017
11	Proanthocyanidins	Biochemical analysis, Antioxidant parameters	Hussein et., al. 2018
12	Betulinic acid	blood glucose level, levels of inflammatory cytokines in serum and kidney tissues, oxidative stress in serum, histopathological changes, protein expressions of Nrf2, HO-1 and phosphorylated AMPK, IκBα, and NF-κB	Xie et., al. 2016
13	Diosgenin	Bodyweight, Kidney Weight, and Excretory Organ Index, Estimations of Plasma Biochemical Parameters, Evaluation of Oxidative Stress, Estimation of Cytokines, Lipid Profile, Biochemical Parameters, Histopathological Studies	Jain et., al. 2020
14	Oleanolic acid	Assessment of renal function, Histological examinations, Transmission electron microscopic examination, Assessment of food and water intake.	Dubey et., al. 2013
15	Melatonin, Quercetin, and Resveratrol	Biochemical evaluations, Antioxidant activity, Histopathological evaluations, Immunohistochemical analysis.	Elbe et., al 2015
16	Enalapril and Paricalcitol	Blood and tissue sampling, Biochemical investigations, Histological and immunohistochemal investigations	Ahmed et., al. 2019
17	Simvastatin	Biochemical assays, Histopathology and immunohistochemistry, Western blot	Rasheed et. al. 2018
18	Ursolic acid	Fasting blood glucose (FBG) measurements, Kidney organ coefficient calculation, Blood urea nitrogen (BUN), serum creatinine (SCr), superoxide dismutase (SOD) and malonaldehyde (MDA) measurements, Western blot, Histopathological examination, Immunohistochemistry examination	Xu et., al. 2018
19	Metformin	Assessment of blood urea nitrogen, serum creatinine, and Microalbuminurea, Determination of adenosine triphosphate and adenosine monophosphate in kidney tissues, Isolation of rat kidney mitochondria, Determination of CoA-SH and acetyl-CoA, Determination of reduced glutathione, Determination of ROS, RNA extraction and cDNA synthesis, Quantification of mRNA expression by real-time polymerase chain reaction (RT-PCR), Histopathology and electron microscopy examination	Alhaider et., al. 2011
20	Diphenyl diselenide	Oral glucose tolerance test, Biochemical index analysis, Measurement of renal and serum oxidative stress markers, Histopathologic examination	Wang et., al. 2021
21	P-Coumaric Acid	Biochemical analysis of serum, Biochemical analysis of urine, Evaluation of oxidative stress parameters, Assessment of kidney hydroxyproline and collagen contents, Evaluation of renal contents of toll like receptor-4, interleukin-6 and transforming growth factor β1, Histopathological examination	Zabad et., al 2019
22	Salidroside	Blood biochemical measurements, Histologic analysis of renal tissues, Western blotting analysis, Enzyme-linked immunosorbent assay	Pei et., al. 2022
23	Aliskiren	Biochemical analysis, Insulin immunoassay, Kidney function tests, Oxidative stress biomarkers, Kidney tumor necrosis factor-alpha, Histopathology	Mahfoz et., al. 2016
24	Myricetin	Biochemical parameters, Kidney glutathione peroxidase activity measurements, Kidney xanthine oxidase/xanthine dehydrogenase enzyme activity measurements, Kidney and plasma malondialdehyde measurements, Kidney xanthine oxidase/xanthine dehydrogenase enzyme activity measurements, Kidney Masson’s trichrome staining.	Ozcan et., al 2011
25	Secoisolariciresinol diglucoside	Estimation of serum glucose, fructosamine, and insulin, Determination of renal function tests, Assessment of renal oxidative stress parameters, cDNA synthesis, Real-time PCR.	Sherif et., al. 2014
26	Formononetin	Physiological parameters, Assessment of kidney function, Cytokine parameters, Histopathological examinations.	Jain et., al. 2014
27	Fucoidan	Chemical Analysis, Physical Activity, Blood Glucose level, Renal Function, Renal Morphological Changes.	Wang et., al 2014
28	Phillyrin	Serum biochemical assay, Histopathological examinations, Measurement of renal oxidative stress, Western blot analysis	Wang et., al. 2021
29	Sinapic Acid	Assessment of Renal Dysfunction, Oxidative and Antioxidant Indices, Cytokine and Inflammatory Marker, Preparation of Total Protein, Cytosol, and Nuclear Protein, Histological Analysis	Alaofi et., al. 2020
30	Apigenin	Analysis of serum and urinary nephrotoxic markers, Biochemical estimation, Tissue preparation and histological analysis, Assessment of proinflammatory and fibrotic markers, TUNEL assay, IHC analysis for detection of apoptosis.	Malik et., al 2017

CONCLUSION:

In the context of the aforementioned studies, it is apparent that any given antioxidant product extends its protective effect through assorted mechanisms. From the above contents, it is clear that most of the natural antioxidants which obtained from crude herbals, extracts, polyherbal formulations, herbo-mineral formulations, etc., have been used in the management of Streptozotocin induced diabetic nephropathy. The parameter evaluated gives the idea about antioxidants while using in further investigation.

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Received on 07.03.2025      Revised on 11.04.2025

Accepted on 07.05.2025 Published on 14.05.2025

Available online from May 16, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(2):131-136.

DOI: 10.52711/2321-5836.2025.00021

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