Kidney Of Streptozotocin-induced Diabetic Rats Research Articles

Effects of resveratrol on biomarkers of oxidative stress and on the activity of delta aminolevulinic acid dehydratase in liver and kidney of streptozotocin-induced diabetic rats

The present study investigated the effects of resveratrol (RV), a polyphenol with potent antioxidant properties, on oxidative stress parameters in liver and kidney, as well as on serum biochemical parameters of streptozotocin (STZ)-induced diabetic rats. Animals were divided into six groups (n = 8): control/saline; control/RV 10 mg/kg; control/RV 20 mg/kg; diabetic/saline; diabetic/RV10 mg/kg; diabetic/RV 20 mg/kg. After 30 days of treatment with resveratrol the animals were sacrificed and the liver, kidney and serum were used for experimental determinations. Results showed that TBARS levels were significantly increased in the diabetic/saline group and the administration of resveratrol prevented this increase in the diabetic/RV10 and diabetic/RV20 groups (P < 0.05). The activities of catalase (CAT), superoxide dismutase (SOD) and aminolevulinic acid dehydratase (δ-ALA-D) and the levels of non protein thiols (NPSH) and vitamin C presented a significant decrease in the diabetic/saline group when compared with the control/saline group (P < 0.05). The treatment with resveratrol was able to prevent these decrease improving the antioxidant defense of the diabetic/RV10 and diabetic/RV20 groups (P < 0.05). In addition, the elevation in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamiltransferase (γ-GT) activities as well as in levels of urea, creatinine, cholesterol and triglycerides observed in the diabetic/saline group were reverted to levels close to normal by the administration of resveratrol in the diabetic/RV10 and diabetic/RV20 groups (P < 0.05). These findings suggest that resveratrol could have a protector effect against hepatic and renal damage induced by oxidative stress in the diabetic state, which was evidenced by the capacity of this polyphenol to modulate the antioxidant defense and to decrease the lipid peroxidation in these tissues.

Proteomic Analysis of Glycated Proteins from Streptozotocin-Induced Diabetic Rat Kidney

Glycation of proteins leading to formation of advanced glycation end products (AGEs) has been considered as one of the important causes of diabetic nephropathy. Therefore, in this study, glycated proteins were detected by anti-AGE antibodies from kidney of streptozotocin-induced diabetic rat showing nephropathic symptoms, by using two dimensional electrophoresis and western blot analysis. These glycated proteins were identified and characterized by using combination of peptide mass finger printing and tandem mass spectrometric approaches. Glycated proteins identified included proteins from metabolic pathways, oxidative stress, cell signaling, and transport. Several of the proteins modified by glycation were involved in glucose metabolism. The extent of glycation was higher in diabetes compared to control, in the glycated proteins that were common to both control and diabetic kidney. Two dimensional electrophoresis proteins profiling of glycated proteins suggest that four of the glycated proteins were significantly up regulated in diabetes.

Determination of time-dependent accumulation of d-lactate in the streptozotocin-induced diabetic rat kidney by column-switching HPLC with fluorescence detection

For better understanding the complete metabolism and the physiological role of d-lactate, the concentrations of d-lactate in the serum, liver and kidney of normal and diabetic rats were determined by our established column-switching HPLC method with pre-column fluorescence derivatization. Eight-week-old male Sprague–Dawley rats were administered with streptozotocin (STZ) (80 mg/kg) or citrate buffer intraperitoneally. The tissues were then removed and homogenized after 4, 8, 12 and 16 weeks of drug administration, respectively. The homogenates were centrifuged at 1200 × g for 10 min, then the supernatants were derivatized with a fluorescent reagent, 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ), separated on an ODS column followed by a Chiralpak AD-RH chiral column for enantioseparation. The results showed that the d-lactate content elevated in all the 3 examined tissues under diabetic stages. In addition, d-lactate concentrations in rat kidney were accumulated significantly and time-dependently in diabetic groups after receiving STZ for 4, 8, 12 and 16 weeks (2.99, 13.11, 18.19, 23.23 vs. 0.79 μmol/mg protein as control group). Moreover, the kidney of induced 12-week diabetic rat renal showed some histological changes of progressive diabetic nephropathy. The results suggest that d-lactate may be used as a marker of diabetic nephropathy.

Comparison of Antioxidant Effects of Honey, Glibenclamide, Metformin, and Their Combinations in the Kidneys of Streptozotocin-Induced Diabetic Rats

Hyperglycemia-induced increase in oxidative stress is implicated in diabetic complications. This study investigated the effect of metformin and/or glibenclamide in combination with honey on antioxidant enzymes and oxidative stress markers in the kidneys of streptozotocin (60 mg/kg; intraperitoneal)-induced diabetic rats. Diabetic rats were randomized into eight groups of five to seven rats and received distilled water (0.5 mL); honey (1.0 g/kg); metformin (100 mg/kg); metformin (100 mg/kg) and honey (1.0 g/kg); glibenclamide (0.6 mg/kg); glibenclamide (0.6 mg/kg) and honey (1.0 g/kg); metformin (100 mg/kg) and glibenclamide (0.6 mg/kg); or metformin (100 mg/kg), glibenclamide (0.6 mg/kg) and honey (1.0 g/kg) orally once daily for four weeks. Malondialdehyde (MDA) levels, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were significantly elevated while catalase (CAT) activity, total antioxidant status (TAS), reduced glutathione (GSH), and GSH:oxidized glutathione (GSSG) ratio was significantly reduced in the diabetic kidneys. CAT, glutathione reductase (GR), TAS, and GSH remained significantly reduced in the diabetic rats treated with metformin and/or glibenclamide. In contrast, metformin or glibenclamide combined with honey significantly increased CAT, GR, TAS, and GSH. These results suggest that combination of honey with metformin or glibenclamide might offer additional antioxidant effect to these drugs. This might reduce oxidative stress-mediated damage in diabetic kidneys.

Ameliorative Effects of Ethanolic Leaf Extract ofAzadirachta indicaon Renal Histologic Alterations in Streptozotocin-Induced Diabetic Rats

We studied the effect of ethanolic leaf extract of Azadirachta indica (AIE) on the microanatomy of the kidney of streptozotocin-induced diabetic rats. Thirty male Wistar rats (161-190 g) were randomly assigned to one of five treatment groups of six animals each: control, diabetic, diabetic + AIE, diabetic + metformin, AIE only. Diabetes was induced with a single intraperitoneal dose of streptozotocin (70 mg/kg body weight). AIE and metformin were administered orally for 50 days (50 d) at 500 mg/kg bw/d and 350 mg/kg bw/d, respectively. Blood glucose was estimated by glucose oxidase method; plasma urea and creatinine were assayed; and paraffin sections of the kidney were stained by periodic acid-Schiff technique. Untreated diabetic rats exhibited marked hyperglycemia. Renal histopathology of these animals showed features of diabetic nephropathy, with nodular glomerulosclerosis and vacuolation of proximal tubule cells (Armanni-Ebstein phenomenon). These feature were absent in the diabetic rats treated with AIE. Besides, plasma urea and creatinine were not significantly different from the control in this group (p > 0.05), in contrast to the untreated diabetic rats, where significant increases in these markers (p < 0.05). These findings showed that the leaf extract of Azadirachta indica ameliorates hyperglycemia and diabetic nephropathy in rats.

Carnosine Prevents Apoptosis of Glomerular Cells and Podocyte Loss in STZ Diabetic Rats

Background/Aims: We identified carnosinase-1 (CN-1) as risk-factor for diabetic nephropathy (DN). Carnosine, the substrate for CN-1, supposedly is a protective factor regarding diabetic complications. In this study, we hypothesized that carnosine administration to diabetic rats might protect the kidneys from glomerular apoptosis and podocyte loss. Methods: We examined the effect of oral L-carnosine administration (1g/kg BW per day) on apoptosis, podocyte loss, oxidative stress, AGEs and hexosamine pathway in kidneys of streptozotocin-induced diabetic Wistar rats after 3 months of diabetes and treatment. Results: Hyperglycemia significantly reduced endogenous kidney carnosine levels. In parallel, podocyte numbers significantly decreased (-21% compared to non-diabetics, p<0.05), apoptotic glomerular cells numbers increased (32%, compared to non-diabetic, p<0.05) and protein levels of bax and cytochrome c increased (175% and 117%). Carnosine treatment restored carnosine kidney levels, prevented podocytes loss (+23% compared to diabetic, p<0.05), restrained glomerular apoptosis (-34% compared to diabetic; p<0.05) and reduced expression of bax and cytochrome c (-63% and -54% compared to diabetics, both p<0.05). In kidneys of all diabetic animals, levels of ROS, AGEs and GlcNAc-modified proteins were increased. Conclusion: By inhibition of pro-apoptotic signaling and independent of biochemical abnormalities, carnosine protects diabetic rat kidneys from apoptosis and podocyte loss.

Expression patterns of ClC-3 mRNA and protein in aortic smooth muscle, kidney and brain in diabetic rats

ClC-3, a member of the ClC family of voltage-gated chloride channels, regulates cell proliferation of cultured rat aortic vascular smooth muscle cells, pathogenesis of allergic rhinitis and tumor cell migration. However, its role in diabetic animals is still unknown. To address this issue, we investigated the expression patterns of ClC-3 in diabetic rats. Five-week-old Sprague-Dawley rats were divided into two groups, 50 non-diabetic control rats (non-DM) and 50 diabetic model rats (DM). ClC-3 mRNA and protein expression in aortic smooth muscle, kidney and brain tissues were examined by fluorimeter-based quantitive RT-PCR assay and Western blot analysis, respectively. ClC-3 mRNA and protein were endogenously expressed in aortic smooth muscle, kidney (cortex and medulla) and brain tissues of both control and streptozotocin-induced diabetic rats. ClC-3 mRNA and protein expression levels were significantly higher in aortic smooth muscle and brain tissues of diabetic rats, but significantly decreased in kidney medulla tissue, relative to non-DM controls. There were no significant differences in ClC-3 mRNA and protein expression in kidney cortex between non-diabetic control and diabetic rats. Furthermore, the altered ClC-3 expression patterns in diabetic rat aortic smooth muscle, brain, and kidney medulla tissues all correlated with the changes in blood glucose levels (p < 0.05). In conclusion, our data show for the first time that diabetes alters both the gene and protein expression of ClC-3 channels. These changes may contribute to the impaired vascular, brain and kidney functions observed in diabetes.

Erratum to: Enhanced expression of naofen in kidney of streptozotocin-induced diabetic rats: possible correlation to apoptosis of tubular epithelial cells

Erratum to: Enhanced expression of naofen in kidney of streptozotocin-induced diabetic rats: possible correlation to apoptosis of tubular epithelial cells

Enhanced expression of naofen in kidney of streptozotocin-induced diabetic rats: possible correlation to apoptosis of tubular epithelial cells

Hyperglycemia/high glucose may induce apoptosis in diabetic kidney, but the mechanism is not fully understood. Naofen was found as a Shiga toxin (Stx)-2-related protein. Based on renal dysfunction in infection with Stx-producing Escherichia coli and on participation of naofen in apoptosis of human embryonic kidney cells, the present study was undertaken to investigate the mechanism of renal dysfunction in diabetes mellitus with particular reference to naofen. In in vivo studies utilizing streptozotocin (STZ)-induced diabetic rats, and also in in vitro cultured rat kidney epithelial (NRK52E) cells, naofen messenger RNA (mRNA) and protein expressions were analyzed. Naofen mRNA location in diabetic kidney was studied by in situ hybridization. Apoptosis was assessed by caspase-3 activity assay. Rat diabetic kidney showed significant increases in caspase-3 activities and naofen mRNA. Naofen was mainly observed at both proximal and distal urinary tubules. Incubation of NRK52E cells in high glucose medium resulted in elevated naofen mRNA expression, whereas neither interleukin-1, interleukin-6, nor tumor necrosis factor-alpha elicited such action. Moreover, treatment of NRK52E cells with naofen small interfering RNA (siRNA) inhibited naofen mRNA expression induced by high glucose and blocked the increase in caspase-3 activity. These data suggest that naofen expression may be upregulated by hyperglycemia, with possible correlation to apoptosis of tubular epithelial cells and thereby to diabetic nephropathy.

The influence of rutin on the extracellular matrix in streptozotocin-induced diabetic rat kidney

We previously reported that rutin administration to streptozotocin (STZ)-induced diabetic rats decreased plasma glucose and increased plasma insulin levels. In this study, we have examined the role of rutin on matrix remodelling in the kidney of STZ-induced diabetic rats. STZ was administered intraperitoneally (50 mg kg(-1)) to male albino Wistar rats to induce experimental diabetes. Rutin (100 mg kg(-1)) was orally administered to normal and STZ-induced diabetic rats for a period of 45 days and its influence on the content of hydroxyproline and collagen and on the activity of matrix metalloproteinases (MMPs) were studied. We have also studied the levels of tissue inhibitors of metalloproteinases (TIMPs) in the kidney. STZ-induced diabetic control rats showed increased content of hydroxyproline and collagen, decreased activity of MMPs and increased levels of TIMPs in the kidney. These changes were positively modulated by rutin treatment in STZ-induced diabetic rats, thereby protecting the kidney. In normal rats treated with rutin, none of the parameters studied were significantly altered. From the results obtained, we could conclude that rutin influences MMPs and effectively protects kidney against STZ-induced damage in rats. The effects observed are due to the reduction of plasma glucose levels by rutin.

Hypoglycemic and Antioxidant Effects of Honey Supplementation in Streptozotocin-induced Diabetic Rats

Oxidative stress plays a crucial role in the development of diabetic complications. The aims of this study were to investigate whether honey could reduce hyperglycemia and ameliorate oxidative stress in kidneys of streptozotocin-induced diabetic rats. Diabetes was induced by a single dose of STZ (60 mg/kg; i. p.). Diabetic rats were randomly grouped and administered distilled water (0.5 mL/day) and honey (0.2 g/kg/day, 1.2 g/kg/day and 2.4 g/kg/day) by oral gavage for four weeks. Each group consisted of six rats. Total antioxidant status (TAS), activities of catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) were significantly reduced, while superoxide dismutase (SOD) activity was up-regulated in kidneys of diabetic rats. Lipid peroxidation (TBARS) and fasting plasma glucose (FPG) were significantly elevated while body weight was reduced in diabetic rats. Honey significantly increased body weight, TAS, activities of CAT, GPx, GR, and GST in diabetic rats. It significantly restored SOD activity, and reduced FPG and TBARS levels in diabetic rats. Histopathological examinations of the kidneys revealed that mesangial matrix expansion and thickening of glomerular basement membrane were reduced in the honey-treated diabetic rats. Honey exerts a hypoglycemic effect and ameliorates oxidative stress in kidneys of streptozotocin-induced diabetic rats.

Decrease of Klotho in the Kidney of Streptozotocin-Induced Diabetic Rats

The klotho gene is expressed in a limited number of tissues, most notably in distal convoluted tubules in the kidney and choroid plexus in the brain. A previous study suggested that Klotho increases resistance to oxidative stress. However, changes of Klotho expression in high glucose-induced oxidative stress remain unclear. In the present study, we used streptozotocin-induced diabetic rats (STZ rats) to examine the effects of insulin, phloridzin or antioxidant, tiron on diabetic nephropathy. Both insulin and phloridzin reversed the lower Klotho expression levels in kidneys of STZ rats by the correction of hyperglycemia. Also, renal functions were improved by these treatments. In addition to the improvement of renal functions, the decrease of Klotho expression in kidney of STZ rats was also reversed by tiron without changing blood glucose levels. The reduction of oxidative stress induced by high glucose can be considered for this action of tiron. This view was further confirmed in vitro using high glucose-exposed Madin-Darby canine kidney (MDCK) epithelial cells. Thus, we suggest that decrease of oxidative stress is not only responsible for the improvement of renal function but also for the recovery of Klotho expression in kidney of STZ rats.

Prostaglandin-Based Renal Protection Against Contrast-Induced Acute Kidney Injury

It has been known for 3 decades that the kidneys rely considerably on a group of prostaglandins that are locally produced in both a constitutive and inducible fashion, primarily in the medulla, to regulate renal blood flow and a variety of functions in tubular cells that occupy that region of the kidney. Arachidonic acid released from phospholipids is converted by cyclooxygenase (COX-1 constitutively, COX-2 inducibly) in the kidney to PGI2, PGE2, PGF2, PGD2, and thromboxane A2. PGE2 and PGF2 are produced predominantly but not exclusively in the renal medulla, whereas degradative enzymes are present in both the cortex and medulla. Prostaglandins enter the tubular lumen by facilitated transport and are partially reabsorbed from the urine in the distal nephron, with urinary levels reflecting renal synthesis. In response to ischemia, vasoconstriction, norepinephrine, or angiotensin II, the kidney increases prostaglandin synthesis to modulate renal vascular resistance with a predominance of PGI2 and PGE2, which are vasodilatory, in contrast to PGF2 and thromboxane, which are vasoconstricting. 1 These actions may be more pronounced in patients with diabetes mellitus because both the endothelial isoform of nitric oxide synthase and the COX-1 and COX-2 enzymes lose their normal regulation in the outer medulla of diabetic rats. 2,3 In addition to these effects in diabetic patients, prostanoids appear to offset the vasoconstrictive effects of iodinated contrast agents. For example, Agmon and coworkers4 examined the effects of vasodilatory prostaglandins on outer medullary blood flow in a rat model of contrast nephropathy and demonstrated that the inhibition of prostanoid production more than doubled the number of necrotic tubules in the outer medulla. Prasad and colleagues 5 measured rat medullary blood flow in real time and demonstrated that prostanoids exert more vasodilatory effects than nitric oxide. These findings illustrate the importance of the prostanoids in maintaining outer medullary blood flow to the kidney. Moreover, these observations provide a physiological basis for the common recommendation that patients discontinue nonsteroidal antiinflammatory agents, which work above and beyond aspirin, before contrast exposure to impair constitutive (COX-1) and inducible (COX-2) production of prostaglandins. Article see p 1793

Effects of combined metformin and honey supplementation on antioxidant enzymes and markers of oxidative stress in kidneys of streptozotocin-induced diabetic rats

Effects of combined metformin and honey supplementation on antioxidant enzymes and markers of oxidative stress in kidneys of streptozotocin-induced diabetic rats

Effects of Malaysian Tualang honey supplementation on glycemia, free radical scavenging enzymes and markers of oxidative stress in kidneys of normal and streptozotocin-induced diabetic rats

Background and aim Hypertension and diabetes mellitus co-exist. It is reported that hypertension is at least twice as common in diabetic subjects when compared with non-diabetic population. Excess generation of free radicals causes oxidative stress which is implicated in the development of hypertension and progression of diabetes as well as its complications. This study investigated the effects of honey on hyperglycemia, antioxidant enzymes, oxidative stress markers and renal histology of normal and streptozotocin (STZ)-induced diabetic rats.

Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney

We recently reported that castration exacerbates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis associated with diabetic renal disease. The aim of the present study was to examine whether these effects of castration can be attenuated with dihydrotestosterone (DHT) supplementation. The study was performed in castrated male Sprague-Dawley, streptozotocin-induced diabetic rats treated with 0 mg/day DHT (DHT(0)), 0.75 mg/day DHT (DHT(0.75)), or 2.0 mg/day DHT (DHT(2.0)) for 14 wk. Treatment with 0.75 mg/day DHT attenuated castration-associated increases in urine albumin excretion (DHT(0), 81.2 +/- 18.1; DHT(0.75), 26.57 +/- 5.8 mg/day; P < 0.05), glomerulosclerosis (DHT(0), 1.1 +/- 0.79; DHT(0.75), 0.43 +/- 0.043 arbitrary units; P < 0.001), tubulointerstitial fibrosis (DHT(0), 1.3 +/- 0.12; DHT(0.75), 1.1 +/- 0.096 AU; P < 0.05), collagen type IV [DHT(0), 3.2 +/- 0.11; DHT(0.75), 2.1 +/- 0.070 relative optical density (ROD); P < 0.01], transforming growth factor-beta (DHT(0), 3.2 +/- 0.16; DHT(0.75), 2.1 +/- 0.060 ROD; P < 0.01), IL-6 (DHT(0), 0.37 +/- 0.011; DHT(0.75), 0.27 +/- 0.014 ROD; P < 0.05), and protein expression and reduced CD68-positive cell abundance (DHT(0), 17 +/- 0.86; DHT(0.75), 4.4 +/- 0.55 cells/mm(2); P < 0.001). In contrast, treatment with 2.0 mg/day DHT exacerbated all these parameters. These data suggest that the detrimental effects of castration in the diabetic kidney can be attenuated with low doses of DHT, whereas high doses augment the adverse effects of castration, and these effects appear to be influenced by estradiol. We conclude that the effects of DHT are dose dependent but caution should be taken when DHT supplementation is considered in the treatment of diabetic renal disease.

Decrease of Bone Morphogenetic Protein-7 (BMP-7) and its Type II Receptor (BMP-RII) in Kidney of Type 1-Like Diabetic Rats

Bone morphogenetic protein-7 (BMP-7) expression is known to be protective for renal damage during diabetic nephropathy and disappears early during the progression of diabetic nephropathy. However, changes in expression of BMP-7 and BMP-7 type II receptor (BMP-RII) during kidney nephropathy response to high glucose-induced oxidative stress remain unclear. In this study, we used streptozotocin-induced diabetic rats with diabetic nephropathy and treated them with insulin, phloridzin, or antioxidant tiron. The insulin, phloridzin, or tiron treatment improved the renal function and decreased fibronectin expression in the streptozotocin-induced diabetic rats. Both insulin and phloridzin could reverse the attenuation effects of hyperglycemia on BMP-7 and BMP-RII expressions in the kidneys of streptozotocin-induced diabetic rats through the correction of hyperglycemia. However, the decrease of BMP-7 and BMP-RII expressions in kidney of streptozotocin-induced diabetic rats could be reversed by tiron through decreasing the high glucose-induced oxidative stress but not through changing the levels of glucose. We further confirmed the effect on reversing the BMP-7 and BMP-RII expressions through decreasing oxidative stress by tiron treatment in high glucose exposed mesangial cells. Thus, we suggest that a decrease in oxidative stress is responsible for the improvement of renal function and recovery of renal BMP-7 and BMP-RII expression in streptozotocin-induced diabetic rats.

Lignin-derived lignophenols attenuate oxidative and inflammatory damage to the kidney in streptozotocin-induced diabetic rats

This study investigated the effects of lignin-derived lignophenols (LPs) on the oxidative stress and infiltration of macrophages in the kidney of streptozotocin (STZ)-induced diabetic rats. The diabetic rats were divided into four groups with 0%, 0.11%, 0.33% and 1.0% LP diets. The vehicle-injected controls were given a commercial diet. At 5 weeks, superoxide (O2−) production, macrophage kinetics, the degree of fibrosis in glomeruli and mRNA expression for monocyte chemoattractant protein-1 (MCP-1) were examined. The NADPH-stimulated O2− levels in the kidney of the diabetic rats treated with 1.0% LP were significantly lower than those in untreated diabetic rats. The number of macrophages, levels of MCP-1 mRNA expression and degree of glomerular fibrosis increased in untreated LP and these levels were significantly lower in 1.0%LP-treated rats. The results suggested that LPs suppress the excess oxidative stress, the infiltration and activation of macrophages and the glomerular expansion in STZ-induced diabetic kidneys.

Determination of Ghrelin Immunoreactivity in Kidney Tissues of Diabetic Rats

Backgrounds/Aims. Ghrelin, a recently discovered hormone, is released largely from stomach and might affect insulin secretion and glucose metabolism. The aim of this study was to determine the immunohistochemical localization of ghrelin in streptozotocin-induced diabetic rat kidneys. Methods. Fifty-four adult male Wistar rats were used in this study. All rats were divided into nine groups according to three time points of the study (2, 4, and 6 weeks) as control group, control group given 0.1 M phosphate-citrate, and diabetic group given 50 mg/kg streptozotocin intraperitoneally. The rats in all groups were decapitated at the end of 2, 4, and 6 weeks of the study. The kidneys of the rats were removed, and tissue samples were processed by using routine paraffin techniques. The samples were immunohistochemically stained using avidin-biotin-peroxidase method for ghrelin immunoreactivity. Results. There were no differences of ghrelin immunoreactivity between the control groups. Ghrelin immunoreactivity was observed in both distal tubulus and collecting ducts in the diabetic groups, while it was detected only in distal tubules of the control groups. The intensity of ghrelin immunoreactivity was increased at 4 and 6 weeks of the study in the diabetic groups. Conclusion. Increased ghrelin immunoreactivity in the diabetic rat kidney tissues suggests that ghrelin may contribute to the pathophysiological mechanism of diabetic nephropathy.

Effects of Sildenafil on Oxidative and Inflammatory Injuries of the Kidney in Streptozotocin-Induced Diabetic Rats

Background: Oxidative stress and inflammation are implicated in the pathogenesis of diabetic nephropathy. Because sildenafil citrate (Viagra®) has variable cardiovascular benefits, including antioxidative and immunomodulating effects, we investigated its influence on oxidative stress and inflammation in diabetic rat kidney. Methods: Streptozotocin-induced diabetic rats received sildenafil (3 mg/kg/day in drinking water) or not (undosed water) for 8 weeks and were compared to age-matched nondiabetic animals. We evaluated 8-hydroxydeoxyguanosine (8-OHdG; for oxidative DNA damage), inducible nitric oxide synthase (iNOS) and nitrotyrosine (for excessive NO production and peroxynitrite formation), and representative chemoattractants [monocyte chemotactic protein-1, MCP-1; for inflammation and monocyte/macrophage infiltrations (ED-1)] in the kidney. Results: Sildenafil-treated rats had a lower kidney-to-body weight ratio than untreated diabetic rats. Urinary albumin excretion in diabetic rats decreased significantly after sildenafil treatment without changes in systolic blood pressure. Sildenafil-treated rats had significantly lower urinary and renal cortical 8-OHdG levels than the nonsildenafil group. Sildenafil administration significantly attenuated the increased renal nitrotyrosine protein expression, positive iNOS and ED-1 staining in glomeruli and tubulointerstitium, and nitrotyrosine staining in tubulointerstitium. Cortical MCP-1 RNA expression in the sildenafil group was significantly lower than in the nonsildenafil group. Conclusions: Sildenafil treatment may attenuate renal damage by ameliorating oxidative and inflammatory injuries in diabetic rats.