Streptozotocin-induced Diabetic Nephropathy In Rats Research Articles

Potential of Bauhinia variegata leaves in the management of diabetic nephropathy

The present study was carried out to explore the potential of aqueous extract of leaves of Bauhinia variegata (AE) in the treatment of streptozotocin-induced diabetic nephropathy in rats. Diabetes was induced in male Sprague Dawley rats with streptozotocin (STZ) at a dose of 55 mg/kg (i.p.). Four weeks after induction of diabetes animals were treated with the extract at a dose of 250, 500 and 1000 mg/kg for 28 days. On the 28th day, biochemical parameters (glucose, glycosylated haemoglobin, total protein, albumin, creatinine, blood urea nitrogen) and urine parameters (total protein, creatinine) were evaluated. After completion of 28 days of treatment, animals were sacrificed and kidneys were isolated. Histopathological evaluation of kidney tissue was carried out by staining the tissue sections with hematoxylin and eosin (HE) stain, Periodic acid–Schiff (PAS) stain and Trichrome stain. Treatment with AE to diabetic rats for 28 days showed a significant decrease in fasting blood glucose, glycosylated haemoglobin, and biochemical parameter like albumin, total protein, creatinine, and blood urea nitrogen (BUN) which is an important marker for the progression of diabetic nephropathy. AE treatment also improved the urine parameters and histological changes in kidney tissue of STZ induced diabetic rats after 28 days of treatment. In-vitro advanced glycation end product inhibitory assay showed that AE possesses AGE inhibitory activity which can play important role in the prevention of DN progression. Present studies proved the potential of aqueous extract of Bauhinia variegata leaves and open a new alternative treatment approach for diabetic nephropathy.

Protective Effect of Saikosaponin D against Streptozotocin-Induced Diabetic Nephropathy in Rats by Regulating the Oxidative Stress and Inflammatory Markers

Protective Effect of Saikosaponin D against Streptozotocin-Induced Diabetic Nephropathy in Rats by Regulating the Oxidative Stress and Inflammatory Markers

Methanolic extract of Merremia emarginata (Burm. f.) Hallier f. attenuates renal damage in streptozotocin-induced diabetic nephropathy in rats

IntroductionMerremia emarginata (syn: Ipomoea reniformis) is used by the traditional healers of the Tirunelveli district of Tamil Nadu and Nelliampathy hills of Kerala for the treatment of diabetes. It contains important phytoconstituents like scopoletin, quercetin, and kaempferol and is reported to have pharmacological activities like antidiabetic antioxidant, antihyperlipidemic, ACE inhibitory, and hypotensive. Diabetic kidney disease is a common microvascular complication seen in patients with long-term diabetes. This study aimed to investigate the efficacy of Merremia emarginata in attenuating diabetic kidney disease. Materials and methodsDiabetes was induced by a single i.p. injection of 55 mg/kg streptozotocin (STZ). The animals were divided into seven groups with six rats in the control group and seven each in the STZ, STZ + Standard drug Ramipril (STD), STZ + Low dose (LD) methanolic extract of Merremia emarginata (MEME), STZ + High dose (HD) MEME, STZ + STD + LD, and STZ + STD + HD groups. The renal function was assessed by estimating various parameters viz, blood glucose, serum and urine creatinine, urine albumin, blood urea nitrogen (BUN), glycosylated haemoglobin (HbA1c) levels, oxidative stress, and kidney hypertrophy. ResultsTreatment with Ramipril and HD MEME showed a decrease in blood glucose levels, urine albumin, a decrease in serum creatinine, an increase in urine creatinine, a decrease in BUN, HbA1c, kidney hypertrophy, and oxidative stress. The combination treatment of Ramipril and HD MEME showed a synergistic effect. ConclusionThe study revealed that MEME attenuates diabetic nephropathy and has the potential to be used in diabetic nephropathy either alone or as an adjuvant.

Phloretamide Protects against Diabetic Kidney Damage and Dysfunction in Diabetic Rats by Attenuating Hyperglycemia and Hyperlipidemia, Suppressing NF-κβ, and Upregulating Nrf2.

Potent hypoglycemic and antioxidant effects were recently reported for the apple-derived phenolic compound phloretamide (PLTM). The renoprotective effects of this compound are yet to be shown. This study aimed to examine the potential of PLTM to prevent diabetic nephropathy in streptozotocin-induced diabetic rats and to examine the possible mechanisms of protection. Non-diabetic and STZ-diabetic male rats were treated orally by gavage with either the vehicle or with PTLM (200 mg/kg; twice/week) for 12 weeks. PTLM significantly increased urine volume and prevented glomerular and tubular damage and vacuolization in STZ-diabetic rats. It also increased creatinine excretion and reduced urinary albumin levels and the renal levels of kidney injury molecule-1 (KIM-1), 8-hydroxy-2'-deoxyguanosine (8-OHdG), neutrophil gelatinase-associated lipocalin (NGAL), and nephrin in the diabetic rats. PTLM also prevented an increase in the nuclear levels of NF-κβ, as well as the total levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), caspase-3, and Bax in the kidneys of diabetic rats. These effects were associated with reduced serum levels of triglycerides, cholesterol, and low-density lipoprotein cholesterol. In both the control and diabetic rats, PTLM significantly reduced fasting plasma glucose and enhanced the renal mRNA and cytoplasmic levels of Nrf2, as well as the levels of Bcl2, superoxide dismutase (SOD), and glutathione (GSH). However, PTLM failed to alter the cytoplasmic levels of keap1 in diabetic rats. In conclusion, PTLM prevents renal damage and dysfunction in STZ-diabetic rats through its hypoglycemic and hypolipidemic activities, as well as through its antioxidant potential, which is mediated by activating the Nrf2/antioxidant axis.

Human umbilical cord mesenchymal stem cell-derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. Currently, there are no effective drugs for the treatment of DN. Although several studies have reported the therapeutic potential of mesenchymal stem cells, the underlying mechanisms remain largely unknown. Here, we report that both human umbilical cord MSCs (UC-MSCs) and UC-MSC-derived exosomes (UC-MSC-exo) attenuate kidney damage, and inhibit epithelial-mesenchymal transition (EMT) and renal fibrosis in streptozotocin-induced DN rats. Strikingly, the Hedgehog receptor, smoothened (SMO), was significantly upregulated in the kidney tissues of DN patients and rats, and positively correlated with EMT and renal fibrosis. UC-MSC and UC-MSC-exo treatment resulted in decrease of SMO expression. Invitro co-culture experiments revealed that UC-MSC-exo reduced EMT of tubular epithelial cells through inhibiting Hedgehog/SMO pathway. Collectively, UC-MSCs inhibit EMT and renal fibrosis by delivering exosomes and targeting Hedgehog/SMO signaling, suggesting that UC-MSCs and their exosomes are novel anti-fibrotic therapeutics for treating DN.

Amorphophallus campanulatus tuber extract protects diabetic nephropathy in streptozotocin-induced diabetic nephropathy rat model by regulating oxidative stress and TNF-α inflammatory pathway.

To assess the effect of Amorphophallus campanulatus tuber (Ac) extract in the protection of diabetic nephropathy in streptozotocin (STZ) induced diabetic nephropathy (DN) rat model. Diabetes was induced with STZ (60 mg/kg, i.p.), and DN was confirmed after six weeks of STZ administration with the estimation of kidney function test. Further rats were treated with Ac 250 and 500 mg/kg p.o. for next four week. Oxidative stress and level of inflammatory cytokines were estimated in the kidney tissue of DN rats. Histopathology of kidney tissue was performed using hematoxylin and eosin staining. There was improvement in the body weight of Ac treated groups than DN group of rats. Blood glucose level was observed to be reduced in Ac treated groups than DN group on 42nd and 70th day of protocol. Treatment with Ac ameliorated the altered level of kidney function tests (creatinine and BUN), enzymes of liver function (aspartate aminotransferase and alanine aminotransferase), and lipid profile in the serum of DN rats. Oxidative stress parameters (malondialdehyde and reactive oxygen species enhances and reduction in the level of glutathione and superoxide dismutase) and inflammatory cytokines such as interleukin-6, tumour necrosis factor-α, and monocyte chemoattractant protein-1 reduces in the tissue of Ac treated group than DN group. Treatment with Ac also attenuates the altered histopathological changes in the kidney tissue of DN rats. The report suggests that Ac protects renal injury in DN rats by regulating inflammatory cytokines and oxidative stress.

Effect of Prunetin on Streptozotocin-Induced Diabetic Nephropathy in Rats - a Biochemical and Molecular Approach.

In the modern era, chronic kidney failure due to diabetes has spread across the globe. Prunetin (PRU), a component of herbal medicines, has a broad variety of pharmacological activities; these may help to slow the onset of diabetic kidney disease. The anti-nephropathic effects of PRU have not yet been reported. The present study explored the potential nephroprotective actions of PRU in diabetic rats. For 28 days, nephropathic rats were given oral doses of PRU (20, 40, and 80 mg/kg). Body weight, blood urea, creatinine, total protein, lipid profile, liver marker enzymes, carbohydrate metabolic enzymes, C-reactive protein, antioxidants, lipid peroxidative indicators, and the expression of insulin receptor substrate 1 (IRS-1) and glucose transporter 2 (GLUT-2) mRNA genes were all examined. Histological examinations of the kidneys, liver, and pancreas were also performed. The oral treatment of PRU drastically lowered the blood glucose, HbA1c, blood urea, creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, lipid profile, and hexokinase. Meanwhile, the levels of fructose 1,6-bisphosphatase, glucose-6-phosphatase, and phosphoenol pyruvate carboxykinase were all elevated, but glucose-6-phosphate dehydrogenase dropped significantly. Inflammatory marker antioxidants and lipid peroxidative markers were also less persistent due to this administration. PRU upregulated the IRS-1 and GLUT-2 gene expression in the nephropathic group. The possible renoprotective properties of PRU were validated by histopathology of the liver, kidney, and pancreatic tissues. It is therefore proposed that PRU (80 mg/kg) has considerable renoprotective benefits in diabetic nephropathy in rats.

Quercetin Mitigates Diabetic Nephropathy in Rats via Keap1/Nrf2/HO-1 Signaling Pathway

A severe diabetic complication, diabetic nephropathy, progresses to terminal kidney disease. A chronic hyperglycemia-related excess of reactive oxygen species results in the advancement of diabetes complications. Through streptozotocin-induced diabetic nephropathy in rats, the present study investigated Quercetin’s renoprotective effect by upregulating nuclear factor-erythroid-related factor 2 (Nrf2) to cope with oxidative stress. During eight weeks study, daily food-water and weekly body weight were evaluated while biochemical, antioxidant parameters and genetic expression (Nrf2, Hemeoxygenease-1, Nuclear factor kappa B, Interlukin-6, and Caspase-3) were assessed at the end. The outcomes were interpreted using ANOVA, and the significance was determined using Dunnett’s test. Quercetin treatment for eight weeks significantly controlled hyperglycemia, dyslipidemia, and downregulated inflammatory activators NFκB, IL-6, and Caspase-3. The significant upregulation of Nrf2 gene expression reduced oxidative damage by promoting Antioxidant response elements and initiating downstream cascade (HO-1 and antioxidant enzymes). The results are supported by histopathology. Experimental evidence suggests that Quercetin can fight metabolic disorders and their related microvascular diseases by activating Nrf2.

Antioxidant phenolic compounds from seeds of Hordeum vulgare Linn. ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats

Antioxidant phenolic compounds from seeds of Hordeum vulgare Linn. ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats

Local anaesthetic procaine derivatives protect rat against diabetic nephropathy via inhibition of DPP-4, inflammation and oxidative stress.

Diabetic nephropathy (DN) is a serious devastating disease. However, the current clinical options to treat DN are not adequate. Thus, in the present study, we intend to develop novel series of procaine-embedded thiazole-pyrazoles as protective agent against DN. The compounds were tested for inhibition of dipeptidyl peptidase (DPP)-4, -8, and - 9 enzyme subtypes, where they selectively and potently inhibit DPP-4 as compared to other subtypes. The top three ranked DPP-4 inhibitors (8i, 8e and 8k) were further screened for inhibitory activity against NF-ĸB transcription. Among these three, compound 8i was identified as the most potent NF-ĸB inhibitor. The pharmacological benefit of compound 8i was further established in streptozotocin-induced diabetic nephropathy in rats. Compound 8i showed marked improvements in blood glucose, ALP, ALT, total protein, serum lipid profile such as total cholesterol, triglyceride, HDL levels and renal functions such as urine volume, urinary protein excretion, serum creatinine, blood urea nitrogen and creatinine clearance as compared to nontreated diabetic control group. It also reduces oxidative stress (MDA, SOD and GPx) and inflammation (TNF-α, IL-1β and IL-6) in the rats as compared to disease control group rats. This study demonstrated the discovery of procaine-embedded thiazole-pyrazole compounds as a novel class of agent against diabetic nephropathy.

Moringa oleifera leaf extract ameliorates early stages of diabetic nephropathy in streptozotocin-induced diabetic rats

Moringa oleifera leaf extract ameliorates early stages of diabetic nephropathy in streptozotocin-induced diabetic rats

Inhibition of dipeptidyl peptidase-4 (DPP4), antioxidant, antiglycation and anti-inflammatory effect of Ferulic acid against streptozotocin toxicity mediate nephropathy in diabetic rats.

The protein glycation due to high blood glucose mediate release of inflammatory intermediate contributes in the development of diabetic nephropathy. Ferulic acid (FA) is a phenolic compound distributed in different foods as whole grains. Inhibitors of DPP4 improve GLP-1-mediated insulin secretion and inhibit liver gluconeogenesis. This study investigated the impact of FA as anti-inflammatory, antioxidant and antiglycation against streptozotocin-induced diabetic nephropathy in rats. This study was carried out on total ninety male rats allocated into six (each 15 rats); group I (control). All other animals (groups II-VI) were receiving 65mg/kg STZ for induction of diabetes. Rats in group II (untreated diabetic). Rats in groups III-V were treated with FA (10, 20, 30mg/kg bw) respectively, i.p. for 8weeks. Group VI received 10 units insulin daily, sc. Fasting blood samples were subjected for assay of glycated hemoglobin (HA1c), serum MDA, aldose reductase, total antioxidant, DPP4 while kidney tissue subjected for assay of malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), IL-1β and AGEs. Data obtained showed that, FA showed antioxidant activity by reducing MDA and enhancement antioxidant activity compared with untreated rats (p < 0.001) with dose dependence. In addition, FA reduced the activities of aldose reductase, DPP4 (p < 0.001), decreased IL-6, TNF-α and AGEs versus untreated rats (p < 0.001). Histological investigation revealed an improvement in the nephron structure in diabetic rat treated with FA versus untreated group. It was concluded that, FA possesses a potent antioxidant and anti-inflammatory and DPP4 inhibitor. For that, it was considered as a protective agent against the risk of diabetic nephropathy and can be used as alternative or complementary supplement.

Anti-angiogenesis and anti-inflammatory effects of Moringa oleifera leaf extract in the early stages of streptozotocin-induced diabetic nephropathy in rats

Objective: To investigate the effect of Moringa oleifera leaf extract on angiogenesis and inflammatory process in a rat model of streptozotocin-induced diabetic nephropathy. Methods: Four weeks after a single injection of 50 mg/kg streptozotocin, rats were treated with 100 or 200 mg/kg/day Moringa oleifera leaf extract, 1 mg/kg/day dapagliflozin, or a combination of Moringa oleifera leaf extract and dapagliflozin for further eight weeks. Renal function, kidney histology, and gene expression were evaluated at the end of the experiment. Results: Renal function of diabetic rats was significantly impaired as evidenced by increased blood urea nitrogen, albuminuria, 24-h proteinuria, and high creatinine clearance which indicated glomerular hyperfiltration. In addition, diabetic rats showed an increase in gene expressions of vascular endothelial growth factor-A (VEGF-A), angiopoietin-2 (Ang2), the Ang2/Ang1 ratio, tumor necrosis factor-α, interleukin-1β and monocyte chemoattractant protein-1. Immunohistochemical staining demonstrated a significant increase in the density of glycoprotein CD34. Moringa oleifera leaf extract markedly improved all renal dysfunction markers and modulated the upregulated expression of angiogenic factors and inflammatory genes. Conclusions: Moringa oleifera leaf extract could suppress abnormal angiogenesis and inflammatory processes possibly by downregulating gene expression of angiogenesis factors and proinflammatory cytokines.

A novel role of Nano selenium and sildenafil on streptozotocin-induced diabetic nephropathy in rats by modulation of inflammatory, oxidative, and apoptotic pathways

AimsThe present study aimed to investigate the effect of nano selenium, sildenafil, and their combination on inflammation, oxidative stress, and apoptosis in streptozotocin-induced diabetic nephropathy in rats. Herein, a new anti-inflammatory pathway for sildenafil as a high-mobility group box (HMGB1) inhibitor was proposed using the molecular docking technique. Materials and methodsRats were divided into 7 groups: normal control, control nano selenium, control sildenafil, control diabetic, diabetic+ nano selenium, diabetic+ sildenafil, diabetic+ nano selenium+ sildenafil. The effects of drugs were evaluated by measuring serum urea, creatinine, lactate dehydrogenase (LDH), levels of tumor necrosis factor-alpha (TNF-α), Interleukin 1 beta (IL-1β), HMGB1, receptor advanced glycation end product (RAGE), malondialdehyde (MDA), thioredoxin reductase (TrxR) by biochemical assays, nuclear factor-kappa b (NF-κB), toll-like receptor (TLR4) by immunohistochemistry, gene expressions of caspase 3 and monocyte chemoattractant protein (MCP-1) besides histopathological investigations of renal cells. Key findingsResults showed beneficial effects of 8 weeks of treatment by nano selenium and sildenafil supported by improvement in kidney function, histopathological changes, and reduction in all of these parameters. These results supported molecular docking that indicated sildenafil had a high binding score and interactions with the HMGB1 receptor. SignificanceThe current study demonstrated a renoprotective effect of nano‑selenium and sildenafil by interfering at multiple pathways, especially the HMGB1/NF-κB signaling pathway.

Ononin mitigates streptozotocin-induced diabetic nephropathy in rats via alleviating oxidative stress and inflammatory markers

ObjectiveDiabetic nephropathy (DN) is a foremost complications among diabetic patients worldwide with growing prevalence and mortality rates annually. Nearly, 25–40% of diabetic patients suffer from DN. ObjectiveThe current research work was done to ascertain the therapeutic properties of ononin against the streptozotocin (STZ)-challenged DN in rats via alleviating oxidative stress and inflammatory responses. MethodologyThe DN was initiated to experimental rats via intraperitoneal injection of 60 mg/kg of STZ. Then DN animals were supplemented orally with three various doses of ononin at 10, 25, and 50 mg/kg once a day for 60 days. After the completion, the glucose level and bodyweight of the animals were recorded. The renal function markers like creatinine, BUN, uric acid, and microalbumin (U-mAlb) was assessed using hematological analyzer. The contents of IL-6, IL-1β, TNF-α, TGF-β1, and fibronectin was assessed using assay kits. The levels of ROS and antioxidant biomarkers were assessed using standard techniques and renal tissues were examined histologically. ResultsThe ononin treatment substantially improved the bodyweight and depleted the FBG level, BUN, creatinine, uric acid, and U-mAlb levels in the STZ-challenged DN animals. The levels of inflammatory and fibrosis factors i.e. IL-6, IL-1β, TNF-α, TGF-β1, and fibronectin was remarkably depleted by the ononin treatment. The ononin also decreased the ROS level and improved the GSH content, SOD and GPx activities in the STZ-challenged DN animals. The findings of histological study also confirmed the therapeutic roles of ononin against STZ-induced changes in renal tissues. ConclusionAltogether, our results from this study evidences the beneficial roles of ononin treatment against the STZ-initiated DN in animals via its antioxidant and anti-inflammatory properties. Hence, it could be the potential candidate in the future for the management of DN.

Rumex nervosus could alleviate streptozotocin-induced diabetic nephropathy in rats by activating Nrf2 signaling.

This study tested the protective effect of Rumex nervous (R. nervosus) methanol extract against streptozotocin (STZ)-mediated type 1 diabetes mellitus (T1DM)-induced nephropathy in rats and examined if this protection involves activating the nuclear factor erythroid 2 related factor-2 (Nrf2). Rats were divided into control, R. nervous (300 mg), STZ (T1DM), STZ + R. nervosus (100, 200, or 300 mg/kg), and STZ + R. nervosus (300 mg/kg) + brusatol (an Nrf2 inhibitor). With no effect on fasting glucose and insulin levels, R. nervosus methanol extract preserved kidney histological structure and alterations kidney function markers (e.g. albumin, creatinine, and urine volume) in the STZ-diabetic rats. R. nervosus also reduced levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukine-6 (IL-6), nuclear levels of the nuclear factor kappa beta (NF-κB), and mRNA of caspase-3 and Bax in the kidneys of these diabetic rats. Concomitantly, it stimulated renal mRNA levels of Bcl2 and Nrf2, cytoplasmic and nuclear levels of Nrf2, and levels of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). All these effects were dose-dependent, with the maximum effect seen with the 300 mg/kg dose, all prevented by brusatol. Also, these effects occurred without any alteration in the transcription of the Kelch-like ECH-associated protein 1 (keap-1). Similar effects on levels of GSH, SOD, CAT, and NF-κB, as well as expression of Nrf2, were also observed in the kidney of control + R. nervous-treated rats. In conclusion, R. nervosus prevents diabetic nephropathy in rats by upregulating and activating Nrf2.

Effects and Mechanism of Ganoderma lucidum Polysaccharides in the Treatment of Diabetic Nephropathy in Streptozotocin-Induced Diabetic Rats.

Ganoderma lucidum polysaccharides (GLP) have renal protection effect but there was no study on the diabetic nephropathy. This study was designed to investigate its effect and mechanism using a diabetic rat model induced by streptozotocin (50 mg/kg, i.p.). The diabetic rats were treated with GLP (300 mg/kg/day) for 10 weeks. The blood glucose, glycated hemoglobin, body weight, and the levels of blood creatinine, urea nitrogen, and urine protein were assessed. And renal pathologies were assessed by the tissue sections stained with hematoxylin-eosin, Masson's trichome, and periodic acid-Schiff. The expression of phosphorylated phosphoinositide 3 kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR), the autophagy proteins beclin-1, LC3-II, LC3-I, and P62; the apoptosis-related proteins caspase-3 and caspase-9; and the inflammation markers IL-6, IL-1β, and TNF-ɑ were assessed. Results showed that GLP alleviated the impairment of renal function by reducing urinary protein excretion and the blood creatinine level and ameliorated diabetic nephropathy. The expression of p-PI3K, p-Akt, and p-mTOR in the diabetic kidney were significantly reduced in the GLP treatment group compared to the without treatment group. GLP treatment activated the autophagy indicators of beclin-1 and the ratio of LC3-II/LC3-I but reduced p62 and also inhibited the expression of caspase-3, caspase-9 and IL-6, IL-1β, and TNF-ɑ. In conclusion, the effect of GLP amelioration diabetic nephropathy may be via the PI3k/Akt/mTOR signaling pathway by inhibition of the apoptosis and inflammation and activation of the autophagy process.

Protective Role of Fisetin in STZ Induced Diabetic Nephropathy in Rats

Objectives: Chronic diabetes mellitus associated with devastating complication the diabetic nephropathy, that further progress to ESRD,a major cause of morbidity and premature mortality in many countries worldwide. Accumulated evidences demonstrated that long standing hyperglycemia induced oxidative stress, inflammatory cytokines, and fibrosis plays a significant role in DN. Fisetin, a bioflavonoid, exhibited variety of promising pharmacological properties such as, anti-diabetic, antioxidant, anti-inflammatory, anti-hyperlipidemic ,and anti-carcinogenics. Hence, the present study was hypothesized to investigate, the effect of fisetin on streptozotocin-induced diabetic nephropathy in rats.&#x0D; Materials and Methods: Sprague Dawley rats were divided into 6 groups (n=6) as normal control, diabetic control (vehicle), Glimepiride (0.5 mg/kg, orally) and Fisetin treatment (2.5, 5 and 10 mg/kg, orally) groups. After the confirmation of diabetes, vehicle/drug treatments were started and continued for 6 weeks. Serum glucose, body weight, were measured on weekly basis.Thereafter, on the last day of treatment protocol, ie 42 day, serum insulin, HbA1c in blood, lipid parameters, creatinine, albumin and urea in serum and in urine creatinine excretion, albumin were measured along with urine volume and creatinine clearance. In addition, weight of kidney and histopathological studies were carried out.&#x0D; Results: Fisetin treatment significantly attenuated reduction in body weight. Also, it significantly decreased the blood glucose level, ameliorate lipid profile and HbA1c (p&lt;0.05) value, but serum insulin level were not much influenced. It also increased albumin in serum, decreased serum urea and creatinine and in urine, it reduced the urine volume, albumin with marked improvement in creatinine excretion and creatinine clearance. Further, the fisetin (10mg/kg) treatment attenuated oxidative stress and cytokines TNF-α (p&lt;0.01), IL-1β (p&lt;0.01), and IL-6 (p&lt;0.05) level in kidney tissue along with amelioration of histopathological alterations compared to diabetic control rats. The standard drug, glimepiride also exhibited similar antidiabetic effect without much influence on oxidative stress, albumin in urine, and cytokine levels.&#x0D; Conclusions: The results indicated that fisetin ameliorated diabetic nephropathy through its antidiabetic and antioxidant effect which may be attributed to inhibition of downward pathway of glycemia induced oxidative stress, inflammation and necroptosis of renal tissue.

Investigation of the impacts of zamzam water on streptozotocin-induced diabetic nephropathy in rats. In-vivo and in-vitro study

BackgroundOxidative stress is considered the main event in the pathogenesis. of diabetic nephropathy (DN). Zamzam water, being natural alkaline with exceptional characteristics, is capable of enhancing antioxidant mechanisms. In this context; the present study has aimed to investigate the protective effects of zamzam water alone or in combination with gliclazide against the streptozotocin (STZ) induced DN model in rats. MethodsDN was initiated by a single intraperitoneal dose of STZ. Three days later, diabetic rats were classified into 5 groups; a normal control group, a diabetic control group, a group receiving gliclazide, a group receiving zamzam water, and a group receiving both gliclazide and zamzam water. Blood pressure (BP) and heart rate (HR) were determined. Then rats were euthanized and serum was isolated for assessment of glucose, insulin, kidney function tests and nitric oxide (NO). Furthermore kidney contents of malondialdehyde (MDA) and reduced glutathione (GSH) were estimated. Histopathology or renal tissues and immunohistochemistry of caspase 3 were determined. In addition, islets of Langerhans were separated from normal rats by collagenase digestion method to study the effects of zamzam water on insulin release in-vitro. Furthermore, chemical analysis of zamzam water has been done. ResultsZamzam water significantly decreased STZ-induced hyperglycemia, BP, HR, oxidative stress biomarkers, impairment in renal functions (urea, creatinine, albumin), morphological changes in kidney and apoptosis. Likewise, zamzam water markedly elevated insulin levels both in in-vivo and in in-vitro experiments. The effects were more pronounced in combination with gliclazide. ConclusionZamzam water has a promising renoprotective effect against STZ induced DN through its anti-diabetic, antioxidant, anti-inflammatory and anti-apoptotic potentials.

Diphenyl diselenide ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats via suppressing oxidative stress and inflammation

Oxidative stress and inflammation are implicated in the occurrence and progression of diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple diaryl diselenide with anti-hyperglycemic, anti-inflammatory, and antioxidant activities. However, the effects of DPDS on DN are still unclear to date. Herein, we aimed to explore whether DPDS could improve renal dysfunction in streptozotocin (STZ)-induced diabetic rats and its underlying mechanisms. STZ-induced DN rats were administered with DPDS (5 or 15 mg/kg) or metformin (200 mg/kg) once daily by intragastric gavage for 12 weeks. DPDS supplementation significantly improved hyperglycemia, glucose intolerance, dyslipidemia, and the renal pathological abnormalities, concurrent with significantly reduced serum levels of creatinine, urea nitrogen, urine volume, and urinary levels of micro-albumin, β2-microglobulin and N-acetyl-glucosaminidase activities. Moreover, DPDS effectively promoted the activities of antioxidant enzymes, and reduced the levels of MDA and pro-inflammatory factors in serum and the kidney. Furthermore, DPDS supplementation activated the renal Nrf2/Keap1 signaling pathway, but attenuated the high phosphorylation levels of NFκB, JNK, p38 and ERK1/2. Altogether, the current study indicated for the first time that DPDS ameliorated STZ-induced renal dysfunction in rats, and its mechanism of action may be attributable to suppressing oxidative stress via activating the renal Nrf2/Keap1 signaling pathway and mitigating inflammation by suppressing the renal NFκB/MAPK signaling pathways, suggesting a potential therapeutic approach for DN.