Injury In Streptozotocin-induced Diabetic Rats Research Articles

Association of Wilms tumor-1 protein in urinary exosomes with kidney injury: a population-based cross-sectional study.

Loss of Wilms tumor-1 (WT1) protein, a podocytopathy marker, through urine exosome (uE), could be an early indication of kidney injury. We examined WT1 in uE (uE-WT1), along with other urine markers of glomerular and kidney tubule injury, in individuals without chronic kidney disease (CKD). The cross-sectional study included individuals who reported having no evidence of chronic kidney disease (CKD). Albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used to assess kidney function. eGFR was calculated using the 2009 CKD-EPI (CKD-Epidemiological) equation. WT1 was analyzed in uE from humans and Wistar rats (before and after the 9th week of diabetes, n = 20). uE-WT1, urinary neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were estimated using ELISA. The Kruskal-Wallis H test, Mann-Whitney U test, and stepwise multivariable linear regression were performed. Urine NGAL and ACR increase with uE-WT1 quartiles (n = 146/quarter). Similarly, uE-WT1, KIM-1, and NGAL were positively associated with ACR. Furthermore, KIM-1, NGAL, and uE-WT1 correlated with ACR. uE-WT1 outperformed KMI-1 and NGAL to explain ACR variability (25% vs. 6% or 9%, respectively). Kidney injury in streptozotocin-induced diabetic rats was associated with a significant rise in uE-WT1. Moreover, the findings were confirmed by the histopathology of kidney tissues from rats. uE-WT1 was strongly associated with kidney function in rats. In individuals without CKD, uE-WT1 outperformed NGAL as a determinant of differences in ACR.

Phoenixin 14 ameloriates pancreatic injury in streptozotocin-induced diabetic rats by alleviating oxidative burden.

Phoenixin-14 (PNX) is a neuropeptide that has been shown to prevent oxidative damage and stimulates insulin secretion. We investigated the effects of PNX on pancreatic injury induced by streptozotocin (STZ), and nicotinamide (NAD). Male Sprague-Dawley rats, in control (C) and diabetic (STZ) groups, were treated with either saline, or PNX (0.45 nmol/kg, or 45 nmol/kg) daily for 3 days 1 week after STZ injection. Fasting blood glucose (FBG) and gastric emptying rate (GER) were measured. Tissue and blood samples were collected. PNX treatments prevented pancreatic damage and β cell loss. Increased luminol and lucigenin levels in the pancreas, ileum and liver tissues of STZ groups were alleviated by PNX treatment in pancreatic and ileal tissues. PNX0.45 decreased FBG without any change in insulin blood level and pancreatic mRNA. GER increased in all diabetic rats while PNX0.45 delayed GER only in the C group. PNX diminishes pancreatic damage and lowers FBG by reducing oxidative load.

Influence of walnut on hepatic ischemia-reperfusion injury in streptozotocin-induced diabetic rats

Nutritional benefits of walnut are well known; however, currently, there is no research showing that walnut can be used as an antioxidant in people with diabetes mellitus (DM). Therefore, the objective of this study was to investigate the protective effects of walnut against oxidative stress in hepatic ischemia-reperfusion (I/R) injury in streptozotocin (STZ) induced diabetic rats. Animals were divided into four-groups (Control, DM, DM+I/R, DM+I/R+Walnut; n=6 each). STZ treatment and I/R procedures were not performed in the control group, other groups were first administered 60-mg/kg STZ intraperitoneally. After 48-h, animals were considered as DM. After four-weeks, DM groups were subjected to 30 min of hepatic-ischemia followed by 45-min reperfusion. DM+I/R+Walnut group was fed pellet-feed mixed with walnut (2 g/100 g/day) until I/R. Other groups were fed only with pellet-feed. At the experimental end, animals decapacitated, blood samples collected to determine serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, malondialdehyde (MDA). Liver samples were collected for histological examinations. Forty-eight-hours after STZ, animals showed significant weight-loss compared to age-matched controls, blood glucose levels were increased (P< 0.05). Four-weeks post-STZ, blood glucose also increased significantly. TNF-α, IL-6, MDA substantially increased in the DM+/I/R group (P< 0.01), whereas in DM+I/R+Walnut group this increase was lesser (P< 0.05). Aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH) levels were lower in DM+/I/R+Walnut vs. DM+I/R groups; but higher than DM/control groups (P< 0.05). Positive-correlation observed between TNF-α and IL-6 (Spearman r:0.793; P< 0.001), and moderately-positive-correlation between IL-6 and LDH (Spearman r:0.429; P< 0.05). Histopathology revealed disordered hepatic lobules, swelling cells, vacuoles in liver specimens visible in the DM+I/R group, implicating hepatic I/R injury, which improved in DM+I/R+Walnut specimens. We conclude that in diabetic rats, hepatic I/R injury is associated with augmented inflammatory response and oxidative stress, while walnut pre-treatment significantly decreased these responses.

Artemisia judaica Attenuates Hyperglycaemia-Mediated Oxidative Stress and Cardiac Injury in Streptozotocin-Induced Diabetic Rats

Artemisia judaica Attenuates Hyperglycaemia-Mediated Oxidative Stress and Cardiac Injury in Streptozotocin-Induced Diabetic Rats

The effect of fullerenol C60 on skeletal muscle after lower limb ischemia reperfusion injury in streptozotocin-induced diabetic rats

Aim: Fullerenol, a water-soluble C60-fullerene, has been demonstrated to scavenge free radicals in vitro and in vivo. The aim of the study was to investigate the effects of fullerenol C60 on lower skeletal muscles in a rat model of ischemia/reperfusion (I/R).Methods: After approval of the ethics committee, 30 Wistar Albino rat were divided into 5 groups with six animals per each as follows: Control (C), diabetes (D), diabetes+fullerenol C60 (DF), diabetes+I/R (group DIR) and diabetes I/R+fullerenol C60 (DIR-F) groups. Streptozotocin was administered to the rats to induce diabetes at a dose of 55 mg/kg. Four weeks after the onset of diabetes, rats were subjected to 2 hours of ischemia and 2 hours of reperfusion. At the end of the reperfusion period, skeletal muscle samples were taken from the lower extremity in all groups for histopathological and immunohistopathological examinations. Results: Myositis and endothelial caspase 3 enzyme activities were high in all groups, particularly DIR. Compared to C, DF and DIR-F groups, inflammation and myositis were significantly higher in the DIR group (P=0.001, P=0.006, P=0.001, respectively, and P=0.001, P=0.022, P=0.001, respectively). Vascular dilatation and congestion were significantly more prominent in all groups compared to the control group (P=0.001 for all).Conclusion: Our results confirm that fullerenol C60 has protective effects against skeletal muscle damage resulting from I/R in diabetic rats. Future studies conducted to evaluate these effects may help illuminate the action mechanism of fullerenol C60 and pathophysiology underlying the tissue damage related to I/R injury.

Anti-inflammatory and Anti-endoplasmic reticulum stress Effects of catalpol Against myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats.

The current study was designed to investigate the effects and the mechanism of catalpol on myocardial ischemia-reperfusion (MI/R) injury in a diabetic rat model. Male Sprague-Dawley rats were divided into DM + sham, DM +I/R, and DM +I/R + C groups and diabetes was induced using single injections of streptozotocin (STZ; 70 mg/kg; i.p). After confirming the induction of diabetes, rats were administered physiological saline and catalpol (10 mg/kg; i.p.) daily for 28 days. Subsequently, rats were subjected to left anterior descending (LAD) coronary artery occlusion for 30 min followed by reperfusion for 2 h. Haemodynamic parameters were recorded throughout surgery, and following sacrifice, hearts were isolated for biochemical, histopathological, and molecular analyses. Catalpol treatment significantly ameliorated MI/R injury by improving cardiac function, normalizing myocardial enzyme activities and markers of oxidative stress, and by maintaining myocardial architecture. Furthermore, expression levels of the inflammatory cytokines TNF-α and IL-6 were decreased in biochemical and immunohistochemical studies. Additionally, the cardioprotective effects of catalpol were partly related to reductions in myocardial endoplasmic reticulum stress (ERS). In conclusion, catalpol exerts cardioprotective effects in diabetic rats by attenuating inflammation and inhibiting ERS.

Ameliorative effect of polydatin on hyperglycemia and renal injury in streptozotocin-induced diabetic rats

To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1β, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin. As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.

Blockade of the Adenosine A3 Receptor Attenuates Caspase 1 Activation in Renal Tubule Epithelial Cells and Decreases Interleukins IL-1β and IL-18 in Diabetic Rats

Diabetic nephropathy (DN) is the main cause of end-stage renal disease, which remains incurable. The progression of DN is associated with progressive and irreversible renal fibrosis and also high levels of adenosine. Our aim was to evaluate the effects of ADORA3 antagonism on renal injury in streptozotocin-induced diabetic rats. An ADORA3 antagonist that was administered in diabetic rats greatly inhibited the levels of inflammatory interleukins IL-1β and IL-18, meanwhile when adenosine deaminase was administered, there was a non-selective attenuation of the inflammatory mediators IL-1β, IL-18, IL-6, and induction of IL-10. The ADORA3 antagonist attenuated the high glucose-induced activation of caspase 1 in HK2 cells in vitro. Additionally, ADORA3 antagonisms blocked the increase in caspase 1 and the nuclear localization of NFκB in the renal tubular epithelium of diabetic rats, both events that are involved in regulating the production and activation of IL-1β and IL-18. The effects of the A3 receptor antagonist resulted in the attenuation of kidney injury, as evidenced by decreased levels of the pro-fibrotic marker α-SMA at histological levels and the restoration of proteinuria in diabetic rats. We conclude that ADORA3 antagonism represents a potential therapeutic target that mechanistically works through the selective blockade of the NLRP3 inflammasome.

Resveratrol alleviates ischemia/reperfusion injury of diabetic myocardium via inducing autophagy.

The rising incidence and complications of diabetes constitutes a major public health issue. The mortality rate of diabetes-induced myocardial ischemia/reperfusion (I/R) injury is significantly elevated. Resveratrol (RSV) is a naturally occurring polyphenol considered to be a potent cardioprotective compound. The aim of the present study was to explore the function and molecular mechanism of RSV on diabetes-induced myocardial I/R injury. Left anterior descending coronary artery ligation was performed to stimulate myocardial I/R injury in streptozotocin-induced diabetic rats. Heart electrical activity was monitored through an electrocardiogram to confirm successful models. The myocardial infarct volume was detected via 2,3,5-triphenyltetrazolium chloride staining. Western blotting was employed to examine the levels of autophagy markers. It was found that the injection of RSV mitigated the ischemia- or I/R injury-induced myocardial damage on hemodynamic function and infarct size, but the autophagy inhibitor 3-methyladenine significantly blocked the function of RSV. Furthermore, the application of RSV significantly enhanced the expression of Beclin-1 and LC-3II but inhibited the serum levels of tumor necrosis factor-α and interleukin-6. These findings revealed an alleviating effect of RSV on diabetes-induced myocardial I/R injury and provided new evidence for the successful application of RSV on the diabetic myocardium.

Ameliorative effects of tropisetron on liver injury in streptozotocin-induced diabetic rats

This study aimed to evaluate the effect of tropisetron on liver injury induced by diabetes. Thirty-five male Wistar rats were assigned to five groups (n = 7): control (C), tropisetron (T), diabetic (D), diabetic + tropisetron (D + T) and diabetic + glibenclamide (D + G). Diabetic rats were treated with tropisetron (3 mg/kg body weight/day) or glibenclamide (1 mg/kg/day) for two weeks. Liver from diabetic rats exhibited a significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), cholesterol (Chol), triglycerides (TG), low-density lipoprotein (LDL), and atherogenic index, and a significant decrease in liver glycogen, serum albumin and high-density lipoprotein. Treatment with tropisetron significantly abrogated diabetes-induced perturbation in these parameters. These effects were equipotent with glibenclamide, suggesting that tropisetron treatment is associated with a hepatoprotective effect against diabetic injury. Therefore, the results of this study manifested the significance of using tropisetron as a promising remedial agent to improve diabetic complications.

Protective effects of resveratrol on hepatic ischemia reperfusion injury in streptozotocin-induced diabetic rats.

Resveratrol (RSV) is a natural polyphenolic compound having antioxidant effects. This study was designed to investigate the protective effects of resveratrol against oxidative stress in hepatic ischemia-reperfusion (I/R) injury in streptozotocin (STZ)-induced diabetic rats. STZ was injected intraperitonally (i.p.) to 18 Sprague-Dawley albino rats, which were divided into three groups, each having six rats. First group was non-treated diabetic group (D), second diabetic group was subjected to 30min of hepatic ischemia followed by a 45-min reperfusion period (D + I/R), and third diabetic group was subjected to 30min of hepatic ischemia followed by a 45-min reperfusion period and treated with 20mg/kg/day oral RSV before 30min I/R injury (D + I/R + RSV). At the end of the experimental period, animals were decapitated, and blood samples were collected to determine tissue tumor necrosis factor-α (TNF-α) levels. Liver and lung tissue samples were obtained for the evaluation of biochemical parameters including malondialdehyde (MDA) and glutathione (GSH) levels and histopathological examinations. Compared to control, I/R injury resulted in decreases in GSH levels and increases in MDA levels. Tissue TNF-α levels were also increased in the D + I/R group compared to D group. Treatment with RSV prevented the alterations on biochemical parameters and histopathological changes induced by I/R. We demonstrate that in diabetic rats, hepatic I/R injury is associated with an augmented inflammatory response and oxidative stress, while RSV pre-treatment significantly decreased these responses. Larger clinical studies are desirable to determine the exact role(s) of RSV on hepatic I/R injury among diabetic subjects.

Pterostilbene Ameliorates Nephropathy Injury in Streptozotocin-Induced Diabetic Rats

Background: Our study investigated the therapeutic role and potential mechanisms of pterostilbene (PS) in diabetic nephropathy (DN) rats. Methods: DN models were established by high-fat diet after streptozotocin injection. A total of 50 Sprague-Dawley rats were randomly divided into control, DN, PS-treated groups (PS-H, PS-M, PS-L). PS was administered to rats by gavage for 8 weeks at 3 different doses (25, 10, and 5 mg/kg/day). The levels of oxidative stress activity (superoxide dismutase [SOD], malondialdehyde [MDA], glutathione peroxidase [GSH-PX]) and inflammatory factors (tumor necrosis factor [TNF]-α, interleukin (IL)-6, IL-1β, monocyte chemoattractant factor [MCP]-1) were detected by ­ELISA. TGF-β, Smad1, and fibronectin (FN) were measured through immunohistochemistry. The relative expressions of phospho-IκBα/IκBα, phospho-IκB kinases (IKK)β/IKKβ, phospho-nuclear factor-κB (NF-κB) p65/NF-κB p65 were detected by western blot. Results: Compared with DN group, the levels of TNF-α, IL-6, IL-1β, and MCP-1 were decreased in the PS-H group (p < 0.05). Meanwhile, the levels of SOD, MDA, GSH-PX improved in kidney and serum in PS-H groups (p< 0.05). PS also significantly decreased the level of phospho-NF-κB p65 and increased the levels of phospho- IKKβ and phospho-Iκ-Bα (p < 0.05). The results showed that PS treatment decreased TGF-β, Smad1, and FN expressions. Conclusion: PS had potential therapeutic effects on DN, which may be related to the regulation of NF-κB pathway.

Effect of dexmedetomidine on ischemia-reperfusion injury of liver and kidney tissues in experimental diabetes and hepatic ischemia-reperfusion injury induced rats

Background: Reperfusion following ischemia can lead to more injuries than ischemia itself especially in diabetic patients. The aim of this study was to evaluate the effect of dexmedetomidine on ischemia-reperfusion injury (IRI) in rats with have hepatic IRI and diabetes mellitus.

Astragalus membranaceus and Panax notoginseng, the Novel Renoprotective Compound, Synergistically Protect against Podocyte Injury in Streptozotocin-Induced Diabetic Rats.

This study was aimed at investigating the synergistical protective effects of Astragalus membranaceus (AG) and Panax notoginseng (NG) on podocyte injury in diabetic rats. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin at 55 mg/kg. Diabetic rats were then orally administrated with losartan, AG, NG, and AG plus NG (2 : 1) for 12 weeks. Albuminuria, biochemical markers, renal histopathology, and podocyte number per glomerulus were measured. Podocyte apoptosis was determined by triple immunofluorescence labeling including TUNEL assay, WT1, and DAPI. Renal expression of nephrin, α-dystroglycan, Bax, Bcl-xl, and Nox4 was evaluated by immunohistochemistry, western blot, and RT-PCR. AG plus NG ameliorated albuminuria, renal histopathology, and podocyte foot process effacement to a greater degree than did AG or NG alone. The number of podocytes per glomerulus, as well as renal expression of nephrin, α-dystroglycan, and Bcl-xl, was decreased, while podocyte apoptosis, as well as renal expression of Bax and Nox4, was increased in diabetic rats. All of these abnormalities were partially restored by AG plus NG to a greater degree than did AG or NG alone. In conclusion, AG and NG synergistically ameliorated diabetic podocyte injury partly through upregulation of nephrin, α-dystroglycan, and Bcl-xl, as well as downregulation of Bax and Nox4. These findings might provide a novel treatment combination for DN.

Reduction of renal tubular injury with a RAGE inhibitor FPS-ZM1, valsartan and their combination in streptozotocin-induced diabetes in the rat

Receptor for advanced glycation end-products (RAGE) is involved in the pathogenesis of diabetic nephropathy. FPS-ZM1, a selective RAGE inhibitor, in combination with valsartan were investigated for their protective potentials on the renal markers of tubular injury in streptozotocin-induced diabetic rats. Rats were assigned into groups of receiving FPS-ZM1 (1 mg/kg/day), valsartan (100 mg/kg/day), and FPS-ZM1 plus valsartan (1 mg/kg/day and 100 mg/kg/day, respectively) for one month. Kidney histology, renal inflammation and oxidative stress, and renal and urinary markers of tubular injury were investigated. FPS-ZM1 and valsartan in combination more significantly attenuated renal expressions of tumor necrosis factor-alpha and interleukin-6 genes and reduced urinary levels of interleukin-6. Moreover, the combination elevated renal NAD+/NADH ratios and Sirt1 activities, and mitigated nuclear acetylated NF-κB p65 levels. In addition to alleviating indices of oxidative stress i.e. malondialdehyde, superoxide dismutase and glutathione peroxidase, the combination of FPS-ZM1 and valsartan more effectively upregulated the renal levels of master antioxidant proteins Nrf2, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase-1. Additionally, this dual therapy ameliorated more efficiently the indices of renal tubular injuries as indicated by decreased renal kidney injury molecule-1 levels as well as reduced urinary levels of cystatin C, retinol binding protein, and beta-2-microglobulin. While FPS-ZM1 alone had no appreciable effects on the renal fibrosis, the combination treatment ameliorated fibrosis better than valsartan in the kidneys. Collectively, these findings underline the extra benefits of FPS-ZM1 and valsartan dual administrations in obviating the renal tubular cell injury in streptozotocin-induced diabetic rats partly by suppressing renal inflammation and oxidative stress.

Empagliflozin Attenuates Renal and Urinary Markers of Tubular Epithelial Cell Injury in Streptozotocin-induced Diabetic Rats

Empagliflozin, a SGLT-2 inhibitor, improves diabetic nephropathy through its pleiotropic anti-inflammatory effects. The present study aims to evaluate empagliflozin effects on renal and urinary levels of tubular epithelial cell injury markers in streptozotocin-induced diabetic rats. Empagliflozin at 10mg/kg (p.o.) was administered for 4weeks, beginning 8weeks after induction of diabetes. Renal function as well as markers of renal tubular epithelial cell injury were assessed in kidney tissue homogenates and urine. Empagliflozin was able to ameliorate diabetes induced elevations in serum cystatin C levels. It also alleviated renal KIM-1/NGAL levels and urinary albumin, α-GST, and RBP excretions. In addition to decreasing urinary levels of cell cycle arrest indices i.e. TIMP-2 and IGFBP7, empagliflozin mitigated acetylated NF-κB levels in renal tissues of diabetic rats. As a whole, these findings reveal empagliflozin capability in improving diabetic nephropathy via ameliorating indices of renal inflammation, injury, and cell cycle arrest on streptozotocin-induced diabetic rats.

Effects of Dexmedetomidine on Renal Ischaemia Reperfusion Injury in Streptozotocin-Induced Diabetic Rats.

The aim of this study was to investigate the effects of dexmedetomidine before and after ischaemia in diabetic rat kidney ischaemia reperfusion (IR) injury in the experimental diabetic rat model. Data belonging to 35 rats weighing between 250 and 300 g were analysed. Diabetes mellitus (DM) was induced using streptozotocin. Groups had bilateral renal vasculature clamped for 45 min ischaemia before clamps were removed, and 4 hours reperfusion was applied. Rats were divided into five groups: Group I or nondiabetic sham group (n=7), Group II or diabetic sham group (n=7), Group III or diabetic IR group (n=7), Group IV or diabetic IR+prophylactic Dex P (before ischaemia) (n=7) and Group V or diabetic IR+therapeutic Dex T (following reperfusion) (n=7). Dexmedetomidine was administered at a dose of 100 μg kg-1 intraperitoneally. Histomorphological and biochemical methods were used to assess the blood and tissue samples. The proximal tubule injury score in the control sham group was significantly lower than in other groups. The proximal tubule and total cell damage scores of the diabetic IR group were significantly higher than the diabetic IR+Dex T group, and no significant difference was detected in the diabetic IR+Dex P group. The biochemical parameters of the IR group were significantly increased compared to Groups I and II; however, there was no significant reduction in these parameters in the groups administered dexmedetomidine. Although administration of dexmedetomidine after ischaemia in the diabetic rat renal IR model was found to be more effective on the histopathological injury scores compared to preischaemic administration, this study has not shown that dexmedetomidine provides effective and complete protection in DM.

Renoprotective effects of dexmedetomidine against ischemia-reperfusion injury in streptozotocin-induced diabetic rats.

BackgroundDiabetic patients are susceptible to renal ischemia-reperfusion injury, which leads to perioperative complications. Activation of NOD-like receptor protein 3 (NLRP3) inflammasome participates in the development of diabetes, and contributes to renal ischemia-reperfusion injury. Dexmedetomidine (DEX), a highly selective α2-adrenoreceptor agonist, shows renoprotective effects against ischemia-reperfusion injury. We aimed to elucidate the effects, underlying mechanisms, and optimal timing of DEX treatment in diabetic rats.MethodsMale Sprague-Dawley rats (n = 12 per group) were randomly divided into normal-sham, diabetes-sham, diabetes-ischemia-reperfusion-control, diabetes-ischemia-reperfusion-DEX-pre-treatment, and diabetes-ischemia-reperfusion-DEX-post-treatment groups. Renal ischemia-reperfusion injury was induced in diabetic rats by occlusion of both renal arteries for 45 min, followed by reperfusion for 24 h. DEX (10 μg/kg) was administered intraperitoneally 1 h before ischemia (pre-treatment) or upon reperfusion (post-treatment). After reperfusion, renal tissue was biochemically and histopathologically evaluated.ResultsDEX treatment attenuated ischemia reperfusion-induced increase in NLRP3, caspase-1, IL-1β, phospho-AKT, and phospho-ERK signaling. Moreover, oxidative stress injury, inflammatory reactions, apoptosis, and renal tubular damage were favorably modulated by DEX treatment. Furthermore, post-reperfusion treatment with DEX was significantly more effective than pre-treatment in modulating NLRP3 inflammasome, AKT and ERK signaling, and oxidative stress.ConclusionsThis study shows that the protective effects of DEX in renal ischemia-reperfusion injury are preserved in diabetic conditions and may potentially provide a basis for the use of DEX in clinical treatment of renal ischemia-reperfusion injury.

Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway

Chronic inflammation plays an essential role in the development of diabetic complications. Understanding the molecular mechanisms that support inflammation is a prerequisite for the design of novel anti-inflammatory therapies. These would take into consideration circulating levels of cytokines and damage-associated molecular patterns (DAMPs) that include the high mobility group box 1 (HMGB1) protein which, in part, promotes the inflammatory response through TLR4 signaling. The liver, as the source of circulating cytokines and acute-phase proteins, contributes to the control of systemic inflammation. We previously found that liver injury in streptozotocin-induced diabetic rats correlated with the level of oxidative stress, increased expression of HMGB1, and with the activation of TLR4-mediated cell death pathways. In the present work, we examined the effects of ethyl pyruvate (EP), an inhibitor of HMGB1 release/expression, on the modulation of activation of the HMGB1/TLR4 inflammatory cascade in diabetic liver. We observed that increased expression of inflammatory markers, TNF-α, IL-6, and haptoglobin in diabetic liver was associated with increased HMGB1/TLR4 interaction, activation of MAPK (p38, ERK, JNK)/NF-κB p65 and JAK1/STAT3 signaling pathways, and with decreased expression of Nrf2-regulated antioxidative enzymes. The reduction in HMGB1 expression as the result of EP administration reduced the pro-inflammatory activity of HMGB1 and exerted a protective effect on diabetic liver, which was observed as improved liver histology and antioxidant and inflammatory statuses. Our results suggest that prevention of HMGB1 release and blockage of the HMGB/TLR4 axis represents a potentially effective therapeutic strategy aimed at ameliorating diabetes-induced inflammation and ensuing liver injury.

Cepharanthine improves glycemic status and slows the progression of renal and vascular injury in streptozotocin‐induced diabetic rats

We have previously demonstrated that Cepharanthine improves glycemic status and reduces renal injury in streptozotocin‐induced diabetic rats via antioxidant and anti‐inflammatory mechanisms. However, the hypoglycemic mechanism of Cepharanthine remains unclear. We hypothesize that Cepharanthine reduces blood glucose in steptozotocin‐induced diabetic rats via restoring pancreatic β‐cells mass and insulin secretion. Diabetes was induced by a single i.p. injection of streptozotocin (50 mg/kg) in male Sprague Dawley rats. Control and diabetic rats were treated with Cepharanthine (10 mg/kg/day, i.p.) for six weeks (n=6–8). Cepharanthine treatment significantly reduced blood glucose levels and increased plasma insulin levels in diabetic rats (blood glucose was 290± 67 in Cepharanthine treated diabetic rats vs. 550±17 mg/dl in non‐treated diabetic rats, P&lt;0.05). The percentage of TUNEL positive cells was significantly elevated in the pancreas of diabetic rats and these changes was reduced by Cepharanthine treatment (P&lt;0.05). Immunohistochemcial analysis revealed a decrease in pancreatic islet‐specific glucose‐6‐phosphatase catalytic subunit related protein (IGRP) and an increase in pancreatic and duodenal homeobox 1 (PDX‐1) expression levels in Cepharanthine treated vs. non treated diabetic rats (P&lt;0.05). Cepharanthine also improved vascular endothelial function as it significantly attenuated the impairment in aortic ring relaxation to acetylcholine in diabetic rats. Moreover, Cepharanthine reduced markers of renal injury and inflammation and slowed the progression of renal fibrosis as evidenced by the reduction in levels of albuminuria, podocalyxin excretion, renal ICAM‐1 and TGF‐β in diabetic rats. The reduction in renal inflammation and injury was associated with decreased in renal caspase 3 expression in Cepharanthine treated diabetic rats. These data suggest that Cepharanthine halts the progression of streptozotocin‐induced diabetic complications in rats via reduced pancreatic β‐cells apoptosis and increased β‐cells maturation and subsequently insulin release probably via the regulation of the PDX‐1 and IGRP transcription factors of pancreatic β‐cells.Support or Funding InformationThe work was supported by bridge funding grant from Augusta University, Augusta, Georgia to Dr. Ahmed A. ElmarakbyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.