Resveratrol, a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats

Diabetic nephropathy is a serious microvascular complication and one of the main causes of end-stage renal disease. Various studies have revealed that increased oxidative stress is a major pathophysiological mechanism which is involved in the etiology of diabetic nephropathy. Resveratrol, a polyphenolic phytoalexin present in red wine, is known to possess potent antioxidant properties and thus we aimed to examine its effect on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. After 4 weeks of STZ injection, rats were divided into four groups: the control rats, diabetic rats and diabetic rats treated with resveratrol (5 and 10 mg/kg, orally) respectively from week 4 up till week 6. At the termination of the experiments, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine and urea clearance were measured. The levels of the renal oxidative stress markers malonaldehyde and glutathione and the antioxidant enzymes superoxide dismutase and catalase were measured in kidney homogenate. STZ-injected rats showed significant increases in blood glucose, polyuria, proteinuria and a decrease in body weight compared with age-matched control rats. After 6 weeks, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance, and proteinuria along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key antioxidant enzymes. Treatment with resveratrol significantly attenuated renal dysfunction and oxidative stress in diabetic rats. The present study reinforces the important role of oxidative stress in diabetic kidney and points towards the possible antioxidative mechanism being responsible for the renoprotective action of resveratrol.     

Quercetin, an anti-oxidant bioflavonoid, attenuates diabetic nephropathy in rats

1. Diabetic nephropathy is an important microvascular complication and one of the main causes of end-stage renal disease. Many in vivo and in vitro studies have indicated that oxidative stress is one of the major pathophysiological mechanisms involved in the development of diabetic nephropathy. In the present study, we examined the effect of an anti-oxidant bioflavonoid quercetin on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. 2. Diabetes was induced in Sprague-Dawley rats with a single intravenous injection of STZ (45 mg/kg). Four weeks after STZ injection, quercetin (10 mg/kg per day) was given orally for 4 weeks in both control and diabetic rats. Plasma glucose levels and bodyweights were measured at 4 and 8 weeks after the STZ injection. At the termination of the experiments, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine and urea clearance were measured. The renal oxidative stress marker malonaldehyde, glutathione levels and the anti-oxidant enzymes superoxide dismutase and catalase were measured in kidney homogenate. 3. Streptozotocin-injected rats showed significant increases in blood glucose, polyuria, proteinuria and a decrease in bodyweight compared with age-matched control rats. After 8 weeks, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance, and proteinuria along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti-oxidant enzymes. Treatment with quercetin significantly attenuated renal dysfunction and oxidative stress in diabetic rats. 4. These results confirm the role of oxidative stress in the development of diabetic nephropathy and point to the possible anti-oxidative mechanism being responsible for the nephroprotective action of quercetin.     

Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats

Chronic hyperglycaemia in diabetes leads to the overproduction of free radicals and evidence is increasing that these contribute to the development of diabetic nephropathy. Among the spices, turmeric (Curcuma longa) is used as a flavouring and colouring agent in the indian diet every day and is known to possess anti-oxidant properties. The present study was designed to examine the effect of curcumin, a yellow pigment of turmeric, on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. Four weeks after STZ injection, rats were divided into four groups, namely control rats, diabetic rats and diabetic rats treated with curcumin (15 and 30 mg/kg, p.o.) for 2 weeks. Renal function was assessed by creatinine, blood urea nitrogen, creatinine and urea clearance and urine albumin excretion. Oxidative stress was measured by renal malonaldehyde, reduced glutathione and the anti-oxidant enzymes superoxide dismutase and catalase. Streptozotocin-injected rats showed significant increases in blood glucose, polyuria and a decrease in bodyweight compared with age-matched control rats. After 6 weeks, diabetic rats also exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance and proteinuria, along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti-oxidant enzymes. Chronic treatment with curcumin significantly attenuated both renal dysfunction and oxidative stress in diabetic rats. These results provide confirmatory evidence of oxidative stress in diabetic nephropathy and point towards the possible anti-oxidative mechanism being responsible for the nephroprotective action of curcumin.     

Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy

We have previously shown that low-dose fenofibrate treatment has an ability to prevent diabetes-induced nephropathy in rats. We investigated here the comparative pre- and post-treatment effects of low-dose fenofibrate (30 mg/kg/day p.o.) in diabetes-induced onset of nephropathy. Rats were made diabetics by single administration of streptozotocin (STZ, 55 mg/kg i.p.). The development of diabetic nephropathy was assessed biochemically and histologically. Moreover, lipid profile and renal oxidative stress were assessed. Diabetic rats after 8 weeks of STZ-administration developed apparent nephropathy by elevating serum creatinine, blood urea nitrogen and microproteinuria, and inducing glomerular-capsular wall distortion, mesangial expansion and tubular damage and renal oxidative stress. Fenofibrate (30 mg/kg/day p.o., 4 weeks) pretreatment (4 weeks after STZ-administration) markedly prevented diabetes-induced onset of diabetic nephropathy, while the fenofibrate (30 mg/kg/day p.o., 4 weeks) post-treatment (8 weeks after STZ-administration) was less-effective. However, both pre-and post fenofibrate treatments were effective in preventing diabetes-induced renal oxidative stress and lipid alteration in diabetic rats though the pretreatment was slightly more effective. Conversely, both pre-and post fenofibrate treatments did not alter elevated glucose levels in diabetic rats. It may be concluded that diabetes-induced oxidative stress and lipid alteration, in addition to a marked glucose elevation, play a detrimental role in the onset of nephropathy in diabetic rats. The pretreatment with low-dose fenofibrate might be a potential therapeutic approach in preventing the onset of nephropathy in diabetic subjects under the risk of renal disease induction. However, low-dose fenofibrate treatment might not be effective in treating the established nephropathy in diabetic subjects.     

Adaptive changes in renal mitochondrial redox status in diabetic nephropathy

Nephropathy is a serious and common complication of diabetes. In the streptozotocin (STZ)-treated rat model of diabetes, nephropathy does not typically develop until 30 to 45 days post-injection, although hyperglycemia occurs within 24 h. We tested the hypothesis that chronic hyperglycemia results in a modest degree of oxidative stress that is accompanied by compensatory changes in certain antioxidants and mitochondrial redox status. We propose that as kidneys progress to a state of diabetic nephropathy, further adaptations occur in mitochondrial redox status. Basic parameters of renal function in vivo and several parameters of mitochondrial function and glutathione (GSH) and redox status in isolated renal cortical mitochondria from STZ-treated and age-matched control rats were examined at 30 days and 90 days post-injection. While there was no effect of diabetes on blood urea nitrogen, measurement of other, more sensitive parameters, such as urinary albumin and protein, and histopathology showed significant and progressive worsening in diabetic rats. Thus, renal function is compromised even prior to the onset of frank nephropathy. Changes in mitochondrial respiration and enzyme activities indicated existence of a hypermetabolic state. Higher mitochondrial GSH content and rates of GSH transport into mitochondria in kidneys from diabetic rats were only partially due to changes in expression of mitochondrial GSH carriers and were mostly due to higher substrate supply. Although there are few clear indicators of oxidative stress, there are several redox changes that occur early and change further as nephropathy progresses, highlighting the complexity of the disease.     

Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine in rats.

Nephrotoxicity is the most common and clinically important side effect of cyclosporine (CsA). Recent evidence suggests that reactive oxygen species (ROS) play an important role in CsA nephrotoxicity. This study was designed to demonstrate the role of oxidative stress and its relation to renal dysfunction and to investigate the effects of quercetin, a bioflavonoid with antioxidant properties, in CsA-induced nephrotoxicity. Quercetin (0.5 and 2.0 mg/kg i.p.) was administered 24 h before and concurrently with CsA (20 mg/kg s.c.) for 21 days. Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS). Renal function was assessed by estimating plasma creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological alterations were assessed histopathologically. Pretreatment with CsA (20 mg/kg s.c.) for 21 days produced elevated levels of TBARS and deteriorated renal function as assessed by increased plasma creatinine, BUN and decreased creatinine and urea clearance as compared to vehicle-treated rats. The kidneys of CsA-treated rats showed severe striped interstitial fibrosis, arteriopathy, glomerular basement thickening, tubular vacuolization and hyaline casts. Quercetin (2 mg/kg) markedly reduced elevated levels of TBARS and significantly attenuated renal dysfunction and morphological changes in CsA-treated rats. It is likely that quercetin, due to its antioxidant properties, prevented CsA-induced ROS and consequently CsA nephrotoxicity. These results clearly demonstrate the pivotal role of oxidative stress and its relation to renal dysfunction, and also point to the therapeutic potential of the natural antioxidant quercetin in CsA-induced nephrotoxicity.     

Tropisetron ameliorates early diabetic nephropathy in streptozotocin‐induced diabetic rats

It has been well established that oxidative stress and inflammation are involved in the pathogenesis of diabetic nephropathy. It has been shown that tropisetron exerts anti‐inflammatory and immunomodulatory properties. The current study was designed to investigate protective effects of tropisetron on early diabetic nephropathy in streptozotocin‐induced diabetic rats. Rats were divided into six groups: (i) untreated diabetic (streptozotocin group); (ii) untreated control; (iii) diabetic rats treated with tropisetron (3 mg/kg); (iv) normal rats treated with tropisetron (3 mg/kg); (v) diabetic rats treated with granisetron (3 mg/kg); and (vi) normal rats treated with granisetron (3 mg/kg); rats began receiving treatment at the time of diabetes induction for 2 weeks. At the termination of the experiments, bodyweight, kidney index, urinary albumin excretion, and glomerular filtration rate were measured. The levels of oxidative stress markers and tumour necrosis factor‐α were also determined. Streptozotocin‐treated animals showed significant loss of bodyweight and renal enlargement and dysfunction. Diabetic rats also exhibited an increase in malondialdehyde along with a significant decrease in glutathione, superoxide dismutase activity, and catalase activity. Furthermore, the diabetic animals demonstrated a significant rise in renal cortical, urinary tumour necrosis factor‐α, and urinary albumin excretion. Both granisetron and tropisetron decreased blood glucose in diabetic animals, but this decrease was not significant for granisetron. Treatment with tropisetron, but not granisetron, prevented increases in oxidative stress and tumour necrosis factor‐α, decreased urinary cytokine excretion and albuminuria, and improved renal morphological damage. In conclusion, the present study suggests that tropisetron may be a protective agent in early diabetic nephropathy, and its action is mediated, at least in part, by anti‐oxidative and anti‐inflammatory mechanisms that appear to be independent of the 5‐HT₃ receptor.     

Mangiferin protects the streptozotocin-induced oxidative damage to cardiac and renal tissues in rats

The role of oxidative stress in streptozotocin (STZ)-induced toxicity and its prevention by a xanthone glucoside, mangiferin was investigated. To induce diabetes mellitus, adult male Wistar rats were injected STZ intravenously at 55 mg/kg body weight. The effect of mangiferin (10 and 20 mg/kg, i.p., 28 days) was investigated in STZ-induced diabetic male rats. Insulin-treated rats (6 U/kg, i.p., 28 days) served as positive control. Diabetic rats given normal saline served as negative control. Normal rats that neither received STZ nor drugs served as normal control. On day 28, the diabetic rats showed significant increase in serum creatine phosphokinase (CPK) and total glycosylated haemoglobin. Kidney revealed tubular degeneration and decreased levels of superoxide dismutase (SOD) and catalase (CAT) with an elevation of malonaldehyde (MDA). Cardiac SOD, CAT and lipid peroxidation were significantly increased. Histopathological findings revealed cardiac hypertrophy with haemorrhages. Analysis of erythrocyte revealed significantly elevated levels of MDA with insignificant decrease in CAT and SOD. Repeated intraperitoneal injections of mangiferin (10 and 20 mg/kg) and insulin (6 U/kg) controlled STZ-induced lipid peroxidation and significantly protected the animals against cardiac as well as renal damage. From the study, it may be concluded that oxidative stress appears to play a major role in STZ-induced cardiac and renal toxicity as is evident from significant inhibition of antioxidant defence mechanism in renal tissue or a compensatory increase in antioxidant defence mechanism in cardiac tissue. Intraperitoneal administration of mangiferin exhibited significant decrease in glycosylated haemoglobin and CPK levels along with the amelioration of oxidative stress that was comparable to insulin treatment.     

氧化应激在糖尿病肾病中的意义及吡格列酮干预研究

目的观察糖尿病大鼠肾脏组织中氧化应激水平,探讨氧化应激在糖尿病肾病中的作用及吡格列酮干预效果。方法采用链脲佐菌素(STZ)诱导糖尿病模型。24只大鼠随机分为正常对照组(NC组)、糖尿病组(DM组)、吡格列酮干预组(3mg·kg-1.d-1,DT组),每组8只。12周末,测定各组相关生化指标。运用比色法检测肾皮质中丙二醛(MDA)的含量、铜锌超氧化物歧化酶(Cu-ZnSOD)及过氧化氢酶(CAT)的活性。结果与NC组相比,DM组和DT组血糖、胆固醇、甘油三酯、尿素氮、血肌酐、肾质量/体质量和尿蛋白定量(24h)值差异有统计学意义。DM组与NC组比较,肾皮质Cu-ZnSOD、CAT活性明显降低(P<0.01),MDA含量明显增加(P<0.01)。DT组与DM组比较,血糖、胆固醇、甘油三酯、尿素氮、血肌酐值差异无统计学意义(P>0.05),肾质量/体质量和尿蛋白定量(24h)明显降低(P<0.05);肾皮质CAT和Cu-ZnSOD活性增加(P<0.05),肾皮质MDA含量降低(P<0.05)。结论糖尿病大鼠肾脏组织中氧化应激水平升高,在糖尿病肾病发病机制中起重要作用。吡格列酮可能通过抗氧化作用改善糖尿病大鼠肾脏损害。     

Short-term melatonin treatment improved diabetic nephropathy but did not affect hemorheological changes in diabetic rats

Increased oxidative stress and hemorheological disturbances may play very important roles in the development of microangiopathies in diabetes mellitus. This study was designed to determine the healing effect of melatonin on hemorheological parameters and diabetic nephropathy in streptozotocin (STZ)-induced diabetic rats. Wistar male rats were divided into four groups as control, untreated-diabetic, melatonin-treated control and melatonin-treated diabetic rats. Diabetes was induced by injecting streptozotocin (45 mg/kg, i.p.). Fourteen weeks after inducement of diabetes, melatonin (10 mg/kg) was administered intraperitoneally for 5 days to the rats. Erythrocyte deformability and aggregation were measured by laser differaction analysis (LORCA). Diabetic nephropathy was assessed by histopathologic evaluation and TUNEL stain in the diabetic kidney. Decreased erythrocyte deformability and increased erythrocyte aggregation indices were determined in the diabetic group. Melatonin treatment did not improve these hemorheological abnormalities. However, renal injuries were diminished in the melatonin-treated diabetic group compared to the untreated diabetic group. Also, melatonin had an antiapoptotic effect on the diabetic kidney. It was concluded that i.p. administration of melatonin for 5 days improved renal injury in diabetic rats, probably by decreasing oxidative stress, but did not affect hemorheological changes.     

Evolution of oxidative stress parameters and response to oral vitamins E and C in streptozotocin-induced diabetic rats

Type I diabetes in humans and streptozotocin (STZ)-induced diabetes in rats has been associated with oxidative stress, but antioxidant therapy has given contradictory results, in part related to the absence of common conditions used to evaluate in-vivo antioxidant properties. This prompted the study of an experimental model of antioxidant therapy in STZ-treated rats. Adult female rats received STZ (50 mgkg(-1)) and were studied 7 or 14 days later. Adipose tissue weight progressively decreased with the time of treatment, whereas plasma triglycerides increased at 7 days, before returning to control values at 14 days after STZ treatment. STZ diabetic rats had increased plasma thiobarbituric acid reacting substances and alpha-tocopherol levels, but the latter variable was decreased when corrected for total lipids. STZ diabetic rats showed a higher GSSG/GSH ratio at Day 14 and lower GSH + GSSG at Day 7 in liver. To evaluate the effect of short-term antioxidant therapy, rats received 5 doses of vitamins C and E over 3 days before being killed on Day 14. Treatment with antioxidants decreased plasma lactic acid and thiobarbituric acid reacting substances, as well as urine 8-isoprostane, and decreased plasma uric acid in controls. Vitamins increased the plasma alpha-tocopherol/lipids ratio only in control rats, although the plasma and liver alpha-tocopherol concentration increased in both groups. STZ diabetic rats showed moderate oxidative stress and treatment with antioxidant vitamins caused a significant change in a selected group of oxidative stress markers, which reflected an improvement in some of the complications associated with this disease. The present experimental conditions can be used as a sensitive experimental model to study the responsiveness of diabetes to other antioxidant interventions.     

N-acetylcysteine prevents nitrosative stress-associated depression of blood pressure and heart rate in streptozotocin diabetic rats

Previous studies have indicated that cardiovascular abnormalities such as depressed blood pressure and heart rate occur in streptozotocin (STZ) diabetic rats. Chronic diabetes, which is associated with increased expression of inducible nitric oxide synthase (iNOS) and oxidative stress, may produce peroxynitrite/nitrotyrosine and cause nitrosative stress. We hypothesized that nitrosative stress causes cardiovascular depression in STZ diabetic rats and therefore can be corrected by reducing its formation. Control and STZ diabetic rats were treated orally for 9 weeks with N-acetylcysteine (NAC), an antioxidant and inhibitor of iNOS. At termination, the mean arterial blood pressure (MABP) and heart rate (HR) were measured in conscious rats. Nitrotyrosine and endothelial nitric oxide synthase (eNOS) and iNOS expression were assessed in the heart and mesenteric arteries by immunohistochemistry and Western blot experiments. Untreated diabetic rats showed depressed MABP and HR that was prevented by treatment with NAC. In untreated diabetic rats, levels of 15-F(2t)-isoprostane, an indicator of lipid peroxidation increased, whereas plasma nitric oxide and antioxidant concentrations decreased. Furthermore, decreased eNOS and increased iNOS expression were associated with elevated nitrosative stress in blood vessel and heart tissue of untreated diabetic rats. N-acetylcysteine treatment of diabetic rats not only restored the antioxidant capacity but also reduced the expression of iNOS and nitrotyrosine and normalized the expression of eNOS to that of control rats in heart and superior mesenteric arteries. The results suggest that nitrosative stress depress MABP and HR following diabetes. Further studies are required to elucidate the mechanisms involved in nitrosative stress mediated depression of blood pressure and heart rate.     

Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and beta-cell damage in rat pancreas.

The aim of the present study was the evaluation of possible protective effects of quercetin (QE) against beta-cell damage in experimental streptozotocin (STZ)-induced diabetes in rats. STZ was injected intraperitoneally at a single dose of 50 mg kg(-1) for diabetes induction. QE (15 mg kg(-1) day, intraperitoneal (i.p.) injection) was injected for 3 days prior to STZ administration; these injections were continued to the end of the study (for 4 weeks). It has been believed that oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). In order to determine the changes of cellular antioxidant defense system, antioxidant enzymes such as glutathione peroxidase (GSHPx), superoxide dismutase (SOD) and catalase (CAT) activities were measured in pancreatic homogenates. Moreover we also measured serum nitric oxide (NO) and erythrocyte and pancreatic tissue malondialdehyde (MDA) levels, a marker of lipid peroxidation, if there is an imbalance between oxidant and antioxidant status. Pancreatic beta-cells were examined by immunohistochemical methods. STZ induced a significant increase lipid peroxidation, serum NO concentrations and decreased the antioxidant enzyme activity. Erythrocyte MDA, serum NO and pancreatic tissue MDA significantly increased (P < 0.05) and also the antioxidant levels significantly decreased (P < 0.05) in diabetic group. QE treatment significantly decreased the elevated MDA and NO (P < 0.05), and also increased the antioxidant enzyme activities (P < 0.05). QE treatment has shown protective effect possibly through decreasing lipid peroxidation, NO production and increasing antioxidant enzyme activity. Islet cells degeneration and weak insulin immunohistochemical staining was observed in STZ induced diabetic rats. Increased staining of insulin and preservation of islet cells were apparent in the QE-treated diabetic rats. These findings suggest that QE treatment has protective effect in diabetes by decreasing oxidative stress and preservation of pancreatic beta-cell integrity.     

Melatonin reduces urinary excretion of N-acetyl-beta-D-glucosaminidase, albumin and renal oxidative markers in diabetic rats

1. Increased oxidative stress has an important role in the pathogenesis of diabetic nephropathy. The aim of the present study was to evaluate diabetic nephropathy by determining markers of oxidative stress and the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), albumin and to investigate the possible protective effects of in vivo melatonin on renal tubular oxidative damage in diabetic rats. 2. Twenty-six rats were randomly divided into three groups: (i) group I, control, non-diabetic rats (n = 9); (ii) group II, untreated diabetic rats (n = 8); and (iii) group III, melatonin-treated diabetic rats (n = 9). In groups II and III, diabetes developed 3 days after administration of a single dose of streptozotocin (35 mg/kg, i.p.). Thereafter, whereas the rats in group II received no treatment, rats in group III began to receive 10 mg/kg per day, i.p., melatonin for 8 weeks. Malondialdehyde (MDA), an index of lipid peroxidation, NAG and microalbumin in the urine, markers of renal tubular damage, were the parameters used for oxidative stress-induced renal injury. Superoxide dismutase (SOD), xanthine oxidase (XO) and glutathione peroxidase (GSH-Px) activities were determined to evaluate changes in the anti-oxidant status of kidney tissue. 3. In untreated diabetic rats, urinary NAG, albumin and renal MDA levels were markedly increased compared with control rats (P < 0.0001). However, these parameters were reduced in diabetic rats by melatonin treatment (P < 0.0001). Urinary excretion of NAG was positively correlated with the microalbuminuria and renal MDA levels (r = 0.8; P < 0.0001). The SOD and XO activities in the untreated diabetic group were found to be significantly higher than those of the control group (P < 0.0001). Superoxide dismutase and XO activities decreased in melatonin-treated rats compared with untreated diabetic rats (P < 0.002 and P < 0.023, respectively). However, the decrease did reach levels seen in control rats. There were no significant differences in GSH-Px activity between the three groups. 4. Therefore, on the basis of these data, we suggest that urinary NAG, albumin excretion, XO activity and MDA levels are more valuable parameters showing the degree of renal tubular injury than classical markers of oxidative stress, including SOD and GSH-Px, in diabetic rat kidneys. Melatonin has an ameliorating effect on oxidative stress-induced renal tubular damage via its anti-oxidant properties. Thus, it may be suggested that urinary NAG excretion and microalbuminuria may be important markers showing the degree of renal changes and the success of long-term treatment of renal impairment with melatonin.     

Kinins are involved in the antiproteinuric effect of angiotensin-converting enzyme inhibition in experimental diabetic nephropathy

The present study examined non-insulin-treated streptozotocin (STZ)-induced diabetic rats to determine the role of kinins in diabetic nephropathy. Their involvement in the renoprotective effect of the angiotensin-converting enzyme inhibitor (ACEI) ramipril was investigated using the bradykinin (BK) B(2)-receptor antagonist, icatibant (HOE 140), or a combination of the two drugs.Although, none of the treatments prevented the decline of the glomerular filtration rate (GFR) in diabetic rats, ramipril (3 mg/kg/day), but not icatibant (HOE 140; 500 microg/kg/day), prevented proteinuria in these animals. However, the antiproteinuric effect of ramipril was reduced by 45% when combined with icatibant. To explore whether the renal kallikrein-kinin system (KKS) belongs to the underlying mechanisms of these findings, we also determined urinary BK levels, renal kallikrein (KLK) and angiotensin-converting enzyme (ACE) activity as well as renal cortical mRNA levels of neutral endopeptidase 24.11 (NEP) and low-molecular weight (LMW) kininogen. STZ led to a reduction of renal KLK and ACE activity and NEP expression and to a three-fold increase of urinary BK excretion and renal kininogen expression. Icatibant given alone had no effect on these parameters. In contrast, ramipril treatment normalized urinary protein and BK excretion as well as kininogen mRNA expression without affecting NEP mRNA expression or KLK and ACE activity.Our data demonstrate that renal BK is increased in severe STZ-induced diabetes mellitus, but may affect glomerular regulation only to a minor degree under this condition. However, kinins are partly involved in the antiproteinuric action of ACEI at this stage of diabetic nephropathy.     

Protective effect of isoliquiritigenin on experimental diabetic nephropathy in rats: Impact on Sirt-1/NFκB balance and NLRP3 expression

The prevalence of diabetes mellitus (DM) drastically increases worldwide. Persistent hyperglycemia affects body microvasculature causing injuries to kidney producing diabetic nephropathy (DNE). Manifestation of these microvascular complications is associated with disturbed redox homeostasis. The current study evaluated the effect of isoliquiritigenin (ISLQ), a bioactive chalcone found in licorice which is known for its antioxidant effect, on diabetes-induced renal injury. DM was prompted in male rats by streptozotocin (STZ, 50 mg/kg, intraperitoneally). ISLQ was administrated by oral gavage for 8 weeks at a dose (20 mg/kg/day). Features of renal injury were observed in kidneys of diabetic rats including, albuminuria and deteriorated renal function. Renal dysfunction was associated with reduced sirtuin-1 (Sirt-1) expression, increased renal oxidative stress, nucleotide-binding domain and leucine-rich repeat containing protein-3 (NLRP3), nuclear factor-κB (NFκB) and inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Moreover, there was significant downregulation of anti-inflammatory cytokine interleukin-10 (IL-10), glomerular and tubular injury and collagen accumulation. ISLQ administration preserved renal function and architecture, restored Sirt1 and renal oxidant-antioxidant balance, dampened inflammation and attenuated collagen accumulation. It can be inferred that ISLQ possess a protective effect and could have a potential as a food supplement to halt development and progression of DNE.     

Effect of edaravone in diabetes mellitus-induced nephropathy in rats

Edaravone, a synthetic-free radical scavenger, has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine and renal vascular resistance. The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats. A single administration of streptozotocin (STZ, 55 mg/kg, i.p.) was employed to induce diabetes mellitus in rats. The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Mean body weight, lipid alteration, renal functional and histopathology were analysed. Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea, and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration. The kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a signifi cant increase in serum triglycerides and decrease in serum high-density lipoproteins. Edaravone (10 mg/kg, i.p., last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities. In addition, its treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins. Interestingly, the renoprotective effect of edaravone was comparable to that of lisinopril (5 mg/kg, p.o, 4 weeks, standard drug). Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus. Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct renoprotection in diabetic rats.     

Effects of linalool on inflammation,matrix accumulation and podocyte loss in kidney of streptozotocin-induced diabetic rats

Abstract

Context: This study aimed to evaluate the renoprotective action of linalool (LIN) on streptozotocin (STZ)-induced diabetic rats.

Objective: The pathological changes in diabetic nephropathy (DN) include oxidative stress, renal injury, matrix accumulation and podocyte abnormalities. We investigated the renoprotective actions of LIN, a monoterpene alcohol, present in herbal essential oils in STZ-induced diabetic rats with renal injury.

Materials and methods: STZ-diabetic rats were administered LIN (25?mg/kg) for 45 days, after which the activities of key enzymes of glucose metabolism, collagen content, oxidative damage and expression of glucose transporter-1 (GLUT-1), transforming growth factor-β₁ (TGF-β₁), nuclear factor-κBp65 (NF-κB p65) and nephrin were analyzed.

Results: Diabetic rats displayed altered glucose metabolism, collagen accumulation and increased TGF-β₁ and NF-κB expression in kidney. LIN treatment restored glucose-metabolizing enzymes, collagen content and GLUT-1 expression and also prevented nephrin loss. LIN also rescued kidney from oxidative stress and inflammation by decreasing the expression of TGF-β₁ and NF-κB. Ultrastructural changes such as basement membrane thickening, reduction in podocyte number and loss of filtration barrier integrity in diabetic rats were mitigated by LIN.

Discussion and conclusion: The results of this study suggest that LIN can attenuate nephropathic changes induced in kidney of diabetic rats. These findings highlight the utility of LIN as a potential drug to treat renal damage in diabetic subjects.     

罗布麻提取物对STZ糖尿病大鼠肾损害的防护作用

本文探讨了罗布麻提取物 (AV) 对STZ大鼠糖尿病肾脏损害的防护作用及部分作用机制。采用链脲佐菌素 (STZ) 诱导大鼠糖尿病模型方法, 观察8周时大鼠血糖、肾功能、氧化应激等指标以及经AV治疗后的变化。结果显示, 糖尿病大鼠的血糖、血尿素氮、24 h尿蛋白含量、尿量、肾脏肥大指数、肾皮质MDA含量显著升高; 肾皮质SOD、GSH活性显著降低。AV干预治疗组的上述指标得到改善, 具有显著性差异。实验结果表明, AV对STZ大鼠糖尿病肾功能有明显的防护作用, 其作用可能与抑制肾脏氧化应激作用有关。     

伊贝沙坦预防链脲佐菌素诱导糖尿病大鼠肾损伤的作用机制(英文)

目的:探讨血管紧张素Ⅱ受体拮抗剂伊贝沙坦(Irb)对链脲佐菌素(STZ)诱导的糖尿病大鼠的肾保护作用机制。方法:SD大鼠随机分为3组:正常对照组(N组,n=7),糖尿病肾病组(DN组,n=6)Irb治疗组(DNI组,n=7)。SD大鼠单侧肾切除后,腹腔注射STZ诱导糖尿病模型,观察治疗后第4, 8,12周的血糖(BG)、体重(BW)、尿白蛋白排泄、24小时尿总蛋白的改变,同时观察12周时肌酐清除率(Ccr)、肾重(KW)、肾脏肥大指数(KW/BW)、肾组织总蛋白含量(RTP)、肾小球面积(A_G)和体积(V_G)、肾小球毛细血管基底膜(GBM)厚度的改变。通过免疫组化观察肾组织结缔组织生长因子(CTGF)和转化生长因子-β_1(TGF-β_1)的表达。结果:DN组和DNI组间BG无差异(p>0.05)。Irb可显著抑制大鼠尿白蛋白、24小时尿总蛋白的排泄,抑制过度增高的Ccr(均为P<0.01)。而且Irb可显著抑制糖尿病大鼠KW、KW/BW、RTP、A_G和V_G的增加(P<0.05或P<0.01)。我们首次证实Irb能够显著抑制GBM的增厚和CTGF的表达(均为P<0.01)。另外,大鼠肾脏CTGF的表达与TGF-β_1的表达和肾小球体积呈显著正相关(均为P<0.01)。结论:早期应用Irb对糖尿病大鼠的肾保护作用可能与抑制肾脏肥大和肾脏CTGF表达有关。