Protective Effects Of Rosiglitazone Research Articles

Abnormal expression of PRKAG2-AS results in dysfunction of cardiomyocytes through regulating PRKAG2 transcription by interacting with PPARG

The role of PRKAG2 in the maintenance of heart function is well established, but little is known about how PRKAG2 is regulated in cardiomyocytes. In this study, we investigated the role of the lncRNA PRKAG2-AS, which is present at the PRKAG2 promoter, in the regulation of PRKAG2 expression. PRKAG2-AS expression was predominantly nuclear, as determined by RNA nucleoplasmic separation and fluorescence in situ hybridization. Knockdown of PRKAG2-AS in the nucleus, but not the cytoplasm, significantly decreased the expression of PRKAG2b and PRKAG2d. Interestingly, we found that PRKAG2-AS and its target genes, PRKAG2b and PRKAG2d, were reduced in the hearts of patients with ischemic cardiomyopathy, suggesting a potential role for PRKAG2-AS in myocardial ischemia. Indeed, knockdown of PRKAG2-AS in the nucleus resulted in apoptosis of cardiomyocytes. We further elucidated the mechanism by which PRKAG2-AS regulates PRKAG2 transcription by identifying 58 PRKAG2-AS interacting proteins. Among them, PPARG was selected for further investigation based on its correlation and potential interaction with PRKAG2-AS in regulating transcription. Overexpression of PPARG, or its activation with rosiglitazone, led to a significant increase in the expression of PRKAG2b and PRKAG2d in cardiomyocytes, which could be attenuated by PRKAG2-AS knockdown. This finding suggests that PRKAG2-AS mediates, at least partially, the protective effects of rosiglitazone on hypoxia-induced apoptosis. However, given the risk of rosiglitazone in heart failure, we also examined the involvement of PRKAG2-AS in this condition and found that PRKAG2-AS, as well as PRKAG2b and PRKAG2d, was elevated in hearts with dilated cardiomyopathy (DCM) and that overexpression of PRKAG2-AS led to a significant increase in PRKAG2b and PRKAG2d expression, indicating that up-regulation of PRKAG2-AS may contribute to the mechanism of heart failure by promoting transcription of PRKAG2. Consequently, proper expression of PRKAG2-AS is essential for maintaining cardiomyocyte function, and aberrant PRKAG2-AS expression induced by hypoxia or other stimuli may cause cardiac dysfunction.

Protective effect of rosiglitazone on microscopic and oxidative stress parameters of ram sperm after freeze-thawing

The purpose of this study was to investigate the effects of rosiglitazone on ram semen after cryopreservation on the quality of thawed sperm. Sperm motility, membrane functionality, viability, total abnormality, acrosome membrane integrity, mitochondrial activity, reactive oxygen species production, ATP content and apoptotic features were assessed after thawing. Rosiglitazone at concentration of 60 µM resulted in the highest (P < 0.05) total motility, progressive motility and straight-line velocity. The percentages of average path velocity and curvilinear velocity were greater in the 60 µM group. Different concentrations of rosiglitazone did not have significant effects on amplitude of the lateral head displacement, linearity and straightness. The highest amounts of membrane functionality and mitochondrial activity after freeze-thawing were observed in groups containing 60 µM. By increasing the rosiglitazone level to 80 µM, no positive effect was observed in most of the evaluated parameters. The lowest ROS concentration was recorded in 60 µM rosiglitazone group (P < 0.05). The group containing 60 µM rosiglitazone also produced the lowest significant percentage of apoptosis-like changes and dead sperm. A greater (P < 0.05) percentage of acrosome integrity in frozen-thawed spermatozoa was observed in the 60 µM rosiglitazone group. There was no significant difference between 40 and 60 µM rosiglitazone in intact acrosome of ram thawed semen. The result showed that supplementation in ram semen extender with rosiglitazone had a positive role in the regulation of ram sperm motility and had strong protective effect on the sperm membrane and acrosome integrity.

Protective effects of rosiglitazone on renal ischemia-reperfusion injury in rats

Objective To explore the protective effect and potential mechanism of rosiglitazone(RGZ)on renal ischemia reperfusion injury. Methods Sixty male SD rats were randomly divided in to sham, kidney ischemia reperfusion injury(IRI), RGZ(10 mg/kg) , RGZ(20 mg/kg), RGZ(40 mg/kg) and RGZ(80 mg/kg)groups(n=10). The model of IRI was induced by clamping the bilateral renal pedicles.ELISA was used to examine the expression of Cr, BUN, IL-8, TNF-α and IL-6 in the serum. RT-PCR was used to detect the mRNA level of IL-8, TNF- and IL-6 in the kidney. The activation of CAT, GPX and SOD were mesaured by xanthine oxidase.The expression of PPAR-γ and p-PPAR-γ were measured by Western blot. The expression of MDA was detected by TBA.The kidney pathological morphology was measured by PAS. Results Compared with the sham group, the kidney pathological injury and the expression of Cr, BUN, IL-8, TNF-α, IL-6, p-PPAR-γ and MDA in the IRI group were significantly increased with decreasing the activation of CAT, GPX and SOD. Compared with the IRI group, the kidney pathological injury and the expression of Cr, BUN, IL-8, TNF-α, IL-6, p-PPAR-γ and MDA in the RGZ group were significantly decreased with increasing the expression of p-PPAR-γ and the activation of CAT, GPX and SOD. There was no difference on the expression of PPAR-γ between three groups. Conclusions RGZ pretreatment can protect rats againest kidney ischemia-reperfusion injury. The mechanism of which is associated with suppressing inflammation and oxidative stress by activating PPAR-γ. Key words: Models, Animal; Rats; Reperfusion Injury; Kidney; Rosiglitazone

Rosiglitazone Suppresses Calcium Oxalate Crystal Binding and Oxalate-Induced Oxidative Stress in Renal Epithelial Cells by Promoting PPAR-γ Activation and Subsequent Regulation of TGF-β1 and HGF Expression.

Peroxisome proliferator-activated receptor- (PPAR-) γ is a ligand-dependent transcription factor, and it has become evident that PPAR-γ agonists have renoprotective effects, but their influence and mechanism during the development of calcium oxalate (CaOx) nephrolithiasis remain unknown. Rosiglitazone (RSG) was used as a representative PPAR-γ agonist in our experiments. The expression of transforming growth factor-β1 (TGF-β1), hepatocyte growth factor (HGF), c-Met, p-Met, PPAR-γ, p-PPAR-γ (Ser112), Smad2, Smad3, pSmad2/3, and Smad7 was examined in oxalate-treated Madin-Darby canine kidney (MDCK) cells and a stone-forming rat model. A CCK-8 assay was used to evaluate the effects of RSG on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were monitored, and lipid peroxidation in renal tissue was detected according to superoxide dismutase and malondialdehyde levels. Moreover, the location and extent of CaOx crystal deposition were evaluated by Pizzolato staining. Our results showed that, both in vitro and in vivo, oxalate impaired PPAR-γ expression and phosphorylation, and then accumulative ROS production was observed, accompanied by enhanced TGF-β1 and reduced HGF. These phenomena could be reversed by the addition of RSG. RSG also promoted cell viability and proliferation and decreased oxidative stress damage and CaOx crystal deposition. However, these protective effects of RSG were abrogated by the PPAR-γ-specific inhibitor GW9662. Our results revealed that the reduction of PPAR-γ activity played a critical role in oxalate-induced ROS damage and CaOx stone formation. RSG can regulate TGF-β1 and HGF/c-Met through PPAR-γ to exert antioxidant effects against hyperoxaluria and alleviate crystal deposition. Therefore, PPAR-γ agonists may be expected to be a novel therapy for nephrolithiasis, and this effect is related to PPAR-γ-dependent suppression of oxidative stress.

Protective effect of rosiglitazone on chronic renal allograft dysfunction in rats

BackgroundChronic renal allograft dysfunction (CRAD) is the main condition affecting the long-term survival of renal allografts. Rosiglitazone, which is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has been shown to exert antifibrotic and anti-inflammatory effects on some renal diseases. The present paper investigates the effect of rosiglitazone on CRAD using a murine model. MethodsThe CRAD group received classical orthotopic F344-Lewis kidney transplantation. The treatment group was treated with rosiglitazone for 12 weeks following renal transplantation. The control subjects were uninephrectomized F344 and Lewis rats. Twelve weeks after the operation, the rats were harvested for renal function, histological, immunohistochemical and molecular biological analyses. ResultsRosiglitazone treatment effectively decreased urine protein excretion and preserved renal function in the CRAD rats. Administration of rosiglitazone also inhibited interstitial fibrosis and macrophage infiltration in the CRAD rat kidneys. Furthermore, rosiglitazone treatment inhibited TGF-β and NF-κB pathway activation, decreased collagen I, collagen IV, α-SMA, MCP-1, ICAM-1, TNF-α, and IL-1β expression, and increased E-cadherin expression in renal allograft tissues from the CRAD rats. ConclusionsRosiglitazone successfully attenuates the development of CRAD via inhibition of TGF-β signaling, the renal tubular epithelial-to-mesenchymal transition (EMT), and inflammation.

Rosiglitazone ameliorates palmitic acid-induced cytotoxicity in TM4 Sertoli cells

The Sertoli cell is the only somatic cell within the seminiferous tubules, and is vital for testis development and spermatogenesis. Rosiglitazone (RSG) is a member of the thiazolidinedione family and is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. It has been reported that RSG protects various types of cells from fatty acid-induced damage. However, whether RSG serves a protective role in Sertoli cells against palmitic acid (PA)-induced toxicity remains to be elucidated. Therefore, the aim of the present study was to investigate the effect of RSG on PA-induced cytotoxicity in Sertoli cells. MTT assay and Oil Red O staining revealed that RSG ameliorated the PA-induced decrease in TM4 cell viability, which was accompanied by an alleviation of PA-induced lipid accumulation in cells. In primary mouse Sertoli cells, RSG also showed similar protective effects against PA-induced lipotoxicity. Knockdown of PPARγ verified that RSG exerted its protective role in TM4 cells through a PPARγ-dependent pathway. To evaluate the mechanism underlying the protective role of RSG on PA-induced lipotoxicity, the present study analyzed the effects of RSG on PA uptake, and the expression of genes associated with both fatty acid oxidation and triglyceride synthesis. The results demonstrated that although RSG did not affect the endocytosis of PA, it significantly elevated the expression of carnitine palmitoyltransferase (CPT)-1A, a key enzyme involved in fatty acid oxidation, which indicated that the protective effect of RSG may have an important role in fatty acid oxidation. On the other hand, the expression of CPT1B was not affected by RSG. Moreover, the expression levels of diacylglycerol O-acyltransferase (DGAT)-1 and DGAT2, both of which encode enzymes catalyzing the synthesis of triglycerides, were not suppressed by RSG. The results indicated that RSG reduced PA-induced lipid accumulation by promoting fatty acid oxidation mediated by CPT1A. The effect of RSG in protecting cells from lipotoxicity was also found to be specific to Sertoli cells and hepatocytes, and not to other cell types that do not store excess lipid in large quantities, such as human umbilical vein endothelial cells. These findings provide insights into the cytoprotective effects of RSG on Sertoli cells and suggest that PPARγ activation may be a useful therapeutic method for the treatment of Sertoli cell dysfunction caused by dyslipidemia.

Protective effect of rosiglitazone on kidney function in high-fat challenged human-CRP transgenic mice: a possible role for adiponectin and miR-21?

Obesity-related albuminuria is associated with decline of kidney function and is considered a first sign of diabetic nephropathy. Suggested factors linking obesity to kidney dysfunction include low-grade inflammation, insulin resistance and adipokine dysregulation. Here, we investigated the effects of two pharmacological compounds with established anti-inflammatory properties, rosiglitazone and rosuvastatin, on kidney dysfunction during high-fat diet (HFD)-induced obesity. For this, human CRP transgenic mice were fed standard chow, a lard-based HFD, HFD+rosuvastatin or HFD+rosiglitazone for 42 weeks to study effects on insulin resistance; plasma inflammatory markers and adipokines; and renal pathology. Rosiglitazone but not rosuvastatin prevented HFD-induced albuminuria and renal fibrosis and inflammation. Also, rosiglitazone prevented HFD-induced KIM-1 expression, while levels were doubled with rosuvastatin. This was mirrored by miR-21 expression, which plays a role in fibrosis and is associated with renal dysfunction. Plasma insulin did not correlate with albuminuria. Only rosiglitazone increased circulating adiponectin concentrations. In all, HFD-induced albuminuria, and renal inflammation, injury and fibrosis is prevented by rosiglitazone but not by rosuvastatin. These beneficial effects of rosiglitazone are linked to lowered miR-21 expression but not connected with the selectively enhanced plasma adiponectin levels observed in rosiglitazone-treated animals.

The protective effect of rosiglitazone on the rats with high altitude pulmonary edema

Objective To investigate the protective effect of rosiglitazone on the rats with high altitude pulmonary edema. Methods Thirty-six SD rats were randomly(random number) divided into 6 groups(n=6 each): control group(Control), hypobaric hypoxia model group(HH), rosiglitazone groups(RSG)which were administered with 3 different doses[RSG-L: 5 mg/(kg·d), RSG-M: 10 mg/(kg·d), RSG-H: 20 mg/(kg·d) ], dexamethasone group[Dex, 4 mg/(kg·d)]. Rats were injected intraperitoneally with different doses of rosiglitazone (RSG), dexamethasone(Dex)or vehicle (Control and HH) for 3 days before placed in simulated altitude of 6 000 m hypobaric hypoxia animal chamber where the temperature and pressure were constant. After 72 h in the chamber, each rat was anesthetized.The water content of lung was determined with wet/dry weight ratio. Bronchoalveolar lavage fluid was measured by bradford method. The contents of GSH was measured by micro-ezymed labeled method. The contents of MDA was measured by TBA method. The enzymatic activities of SOD was measured by WST-1 method.The changes of the TNF-α, IL-6 and IL-10 in serum were determined by ELISA.Light microscope was used to observe the pathological changes of lung tissue. Results Compared with Control group, the wet/dry weight ratio of lung(5.08±0.24) and total protein content of BALF(351.06±44.55)μg/mL increased significantly (P<0.01) in HH group. There were red blood cells in the alveolar and interstitium, pink fluid exudation in the alveolar, the alveolar septum enhancement, and a large number of inflammatory cell infiltration; the SOD activity(10.65±0.94)U/mgprot and the content of GSH(1.63±0.20)μmol/gprot in lung tissue were significantly decreased (P<0.01), the contents of MDA(2.15±0.18)nmol/mgprot increased significantly (P<0.01), TNF-α(56.92±2.87)pg/mL and IL-6(217.80±48.01)pg/mL levels in serum were significantly increased (P<0.01), and IL-10(76.85±16.72)pg/mL level decreased (P<0.05). Compared with the HH group, the wet/dry ratio of lung and total protein content of BALF in different doses of rosiglitazone group significantly decreased (P<0.01), the pathological changes of the lung tissue was significantly improved, SOD activity and the content of GSH in lung tissue was significantly increased (P<0.01), the content of MDA decreased (P<0.01), The levels of TNF-α and IL-6 in serum were significantly decreased (P<0.01), while the IL-10 level was significantly increased (P<0.01). Conclusion Rosiglitazone could protect the high altitude pulmonary edema by alleviating the oxidative stress and inflammatory response. Key words: Rosiglitazone; High altitude pulmonary edema; Oxidative stress; Inflammation; Rat

Protective effect of rosiglitazone against acetaminophen-induced acute liver injury is associated with down-regulation of hepatic NADPH oxidases

The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. The aim of the present study was to investigate the effects of rosiglitazone (RSG), a synthetic PPAR-γ agonist, on acetaminophen (APAP)-induced acute liver injury. Male CD-1 mice were injected with APAP (300mg/kg). Some mice were pretreated with RSG (20mg/kg) 48, 24 and 1h before APAP injection. As expected, RSG pretreatment alleviated APAP-induced acute liver injury. Moreover, RSG pretreatment attenuated APAP-induced hepatic cell death and improved the survival. Although it did not affect hepatic cytochrome P450 (CYP)2E1 expression, RSG pretreatment attenuated reduction of hepatic glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd) and glutathione S-transferase (GST) activities, inhibited upregulation of hepatic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-2 and NOX-4, and alleviated hepatic GSH depletion during APAP-induced acute liver injury. In addition, RSG pretreatment suppressed activation of hepatic nuclear factor kappa B (NF-κB) and extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling during APAP-induced acute liver injury. These results provide a novel mechanistic explanation for RSG-mediated protection against APAP-induced acute liver injury. The present results suggest that synthetic PPAR-γ agonists might be effective agents for preventing the progression of APAP-induced acute liver injury.

Rosiglitzone Suppresses Angiotensin II-Induced Production of KLF5 and Cell Proliferation in Rat Vascular Smooth Muscle Cells

Krüppel-like factor (KLF) 5, which initiates vascular smooth muscle cell (VSMC) proliferation, also participates in Angiotensin (Ang) II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, in aortas of Ang II-infused rats, vascular remodeling and KLF5 expression were markedly increased, and its target gene cyclin D1 was overexpressed. Co-treatment with rosiglitazone diminished these changes. In growth-arrested VSMCs, PPAR-γ agonists (rosiglitazone and 15d-PGJ2) dose-dependently inhibited Ang II-induced cell proliferation and expression of KLF5 and cyclin D1. Moreover, these effects were attenuated by the PPAR-γ antagonists GW9662, bisphenol A diglycidyl ether and PPAR-γ specific siRNA. Furthermore, rosiglitazone inhibited Ang II-induced phosphorylation of protein kinase C (PKC) ζ and extracellular signal-regulated kinase (ERK) 1/2 and activation of early growth response protein (Egr). In conclusion, in Ang II-stimulated VSMCs, rosiglitazone might have an antiproliferative effect through mechanisms that include reducing KLF5 expression, and a crosstalk between PPAR-γ and PKCζ/ERK1/2/Egr may be involved in. These findings not only provide a previously unrecognized mechanism by which PPAR-γ agonists inhibit VSMC proliferation, but also document a novel evidence for the beneficial vascular effect of PPAR-γ activation.

Rosiglitazone, a PPARγ agonist, ameliorates palmitate-induced insulin resistance and apoptosis in skeletal muscle cells.

Palmitate induces insulin resistance and apoptosis in insulin target tissues. Rosiglitazone (RSG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, can activate both pro-apoptotic and anti-apoptotic pathways in different cells; however, its effect on palmitate-induced apoptosis in skeletal muscle cells remains to be elucidated. After differentiation of C2C12 cells, myotubes were treated with palmitate, RSG and GW9662 (PPARγ antagonist). MTT and terminal deoxynucleotide transferase dUTP nick end labelling (TUNEL) assays and caspase-3 activity were used to investigate the apoptosis. To study the underlying mechanism, glucose uptake, gene expression and protein levels were evaluated. A total of 0.75 mM palmitate reduced cell viability by 43% and increased TUNEL-positive cells and caspase-3 activity by 15-fold and 6.6-fold, respectively. RSG (10 μM) could markedly decrease the level of TUNEL-positive cells and caspase-3 activity in palmitate-treated cells. The protective effect of RSG on apoptosis was abrogated by GW9662. To investigate the molecular mechanism of this effect, gene expression and protein level of protein tyrosine phosphatase 1B (PTP1B) were evaluated. Palmitate and RSG individually increased the expression and protein level of PTP1B, whereas combined treatment (palmitate and RSG) were able to further increase the expression of PTP1B in C2C12 cells. We also evaluated the effect of RSG on palmitate-induced insulin resistance in muscle cells. RSG could significantly improve glucose uptake by 0.4-fold in myotubes treated with palmitate. Moreover, RSG could restore the phosphorylation of Akt in palmitate-treated cells. These data suggest that RSG protects skeletal muscle cells against palmitate-induced apoptosis and this effect appears to be mediated via the PPARγ-dependent and PTP1B-independent mechanisms. Saturated free fatty acids (FFAs), such as palmitate, have been shown to induce cellular apoptosis. Strategies for preventing the cytotoxic effect of palmitate are useful in reduction of diabetes complications. In this study, we introduced RSG as an agent that protects skeletal muscle cells against palmitate-induced apoptosis and insulin resistance. It appears that RSG protects skeletal muscle cells against palmitate-induced apoptosis via the PPARγ-dependent and PTP1B-independent mechanisms. Given the role of FFAs in skeletal muscle apoptosis, these findings support the idea that RSG can ameliorate diabetes complications such as skeletal muscle loss.

Neuroprotective effects of PPAR‐γ agonist rosiglitazone in N171‐82Q mouse model of Huntington's disease

Huntington's disease (HD) is a devastating genetic neurodegenerative disease caused by CAG trinucleotide expansion in the exon-1 region of the huntingtin gene. Currently, no cure is available. It is becoming increasingly apparent that mutant Huntingtin (HTT) impairs metabolic homeostasis and causes transcriptional dysregulation. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a transcriptional factor that plays a key role in regulating genes involved in energy metabolism; recent studies demonstrated that PPAR-γ activation prevented mitochondrial depolarization in cells expressing mutant HTT and attenuated neurodegeneration in various models of neurodegenerative diseases. PPAR-γ-coactivator 1α (PGC-1 α) transcription activity is also impaired by mutant HTT. We now report that the PPAR-γ agonist, rosiglitazone (RSG), significantly attenuated mutant HTT-induced toxicity in striatal cells and that the protective effect of RSG is mediated by activation of PPAR-γ. Moreover, chronic administration of RSG (10 mg/kg/day, i.p) significantly improved motor function and attenuated hyperglycemia in N171-82Q HD mice. RSG administration rescued brain derived neurotrophic factor(BDNF) deficiency in the cerebral cortex, and prevented loss of orexin-A-immunopositive neurons in the hypothalamus of N171-82Q HD mice. RSG also prevented PGC-1α reduction and increased Sirt6 protein levels in HD mouse brain. Our results suggest that modifying the PPAR-γ pathway plays a beneficial role in rescuing motor function as well as glucose metabolic abnormalities in HD.

Effect of rosiglitazone on rabbit model of myocardial ischemia-reperfusion injury

ObjectiveTo explore mechanism and protective effect of rosiglitazone on myocardial ischemia reperfusion (I/R) injury. MethodsA total of 48 male Japanese white big-ear rabbits were randomly divided into control group (A), I/R group (B), low dose of rosiglitazone group (C), high dose of rosiglitazone group (D). Plasma concentration of and also reduced the concentration of plasma serum creatine kinase (CK), CK-MB, high-sensitivity C-reactive protein (hsCRP), ultra-superoxide dismutase (SOD), malondialdehyde (MDA), lactic acid glutathione skin peroxidase (GSH-PX), nitric oxide (NO) and endothelin (ET) were measured 1 h later after I/R. Twenty-four hours after I/R the hearts were harvested for pathological and ultrastructural analysis. Area of myocardial infarction were tested. ResultsPlasma concentration of CK, CK-MB, hsCRP, NO, MDA and ET were decreased in C, D group compared with group B. Plasma concentration of T-SOD and GSH-Px were increased significantly in C, D group compared with group B. Compared with group B, pathological and ultrastructural changes in C and D group were slightly. There was significant difference in myocardial infarction area between group C, D and group B (P<0.05). Myocardial infarction area and arrhythmia rate were lower in group C, D compare with group B. ConclusionsRosiglitazone may protect myocardium from I/R injury by enhancing T-SOD and GSH-Px concentration, inhibit inflammatory reaction, and improve endothelial function.

Metabonomic investigation on the protective effects of rosiglitazone and caloric restriction for renal senescence in a rat model

Metabonomic investigation on the protective effects of rosiglitazone and caloric restriction for renal senescence in a rat model

Effect of rosiglitazone on the expression of cardiac adiponectin receptors and NADPH oxidase in type 2 diabetic rats

This study investigated the effect of rosiglitazone on the expression of cardiac adiponectin receptors and NADPH oxidase in type 2 diabetic rats. Thirty-six male Wistar rats were randomly divided into control (C, n=10), diabetic (D, n=13) and diabetic treated with rosiglitazone (DT, n=13). Type 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of a low dose of streptozotocin (STZ). Eleven rats in diabetic untreated group and twelve rats in diabetic treated group were successfully induced to be diabetes. After induction of diabetes, rosiglitazone (3mg/kg/day) was administrated to diabetic treated rats by gavage for 12weeks. Twelve weeks later, the heart function was detected. Plasma and myocardial adiponectin levels were detected by enzyme linked immunosorbent assay (ELISA). The cardiac mRNA expression of adiponectin receptors 1 and 2, and monocyte chemoattractant protein-1 (MCP-1) was assayed by reverse transcript-polymerase chain reaction (RT-PCR). The cardiac mRNA expression of p22phox and NOX4 was assayed by real-time fluorescence quantitative PCR. The cardiac protein expression of phosphor-AMPK-α (Thr172) and glucose transporter 4 (GLUT4) was determined by Western blotting. The protein expression of adiponectin receptors 1 and 2, and connective tissue growth factor (CTGF)were determined by immunohistochemistrial staining. The ratio of heart weight to body weight was significantly increased in diabetic rats compared to control. Heart function, plasma and myocardial adiponectin levels, the protein and mRNA expression of myocardial adiponectin receptors 1 and 2, myocardial phosphorylation of AMPK-α (Thr172) and the protein expression of myocardial GLUT4 were significantly decreased in diabetic rats compared to control (P<0.05). The expression of myocardial p22phox, Nox4, MCP-1 and CTGF was significantly increased in diabetic rats compared to control (P<0.05). Rosiglitazone treatment significantly attenuated the increased ratio of heart weight to body weight, and the increased expression of myocardial p22phox, Nox4, MCP-1 and CTGF in diabetic rats (P<0.05). Heart function, plasma and myocardial adiponectin levels, the expression of myocardial adiponectin receptors 1 and 2 and GLUT4, and myocardial phosphorylation of AMPK-α (Thr172) were significantly decreased in diabetic treated with rosiglitazone compared to diabetic untreated (P<0.05). These results suggest that the protective effects of rosiglitazone on diabetic rat hearts may be attributable to the increased myocardial adiponectin and its receptors and the decreased myocardial NADPH oxidase.

Rosiglitazone protection against experimentally-induced intestinal ischemia/re-perfusion

Several studies have shown that peroxisome proliferator-activated receptor-g (PPARg) agonists protect against ischemia/re-perfusion (I/R) damage in different organs. This study was carried out to assess the possible role of PPARg on intestinal I/R-mediated tissue injury. This was achieved by evaluating the effects of the PPARg agonist rosiglitazone and the PPARg antagonist bisphenol A diglycidyl ether (BADGE) on experimentally-induced intestinal I/R. The possible underlying mechanisms, including changes in the release of NO and/or inflammatory cytokines (such as tumor necrosis factor-alpha, TNFa), infiltration of neutrophils, and apoptotic cell death were investigated. Rats were divided into sham-operated and I/R groups. The I/R group was further divided into sub-groups, and these rats were treated 30 min before induction of ischemia with rosiglitazone, BADGE, or a combination of BADGE + rosiglitazone; control rats received vehicle in place of the drugs. Intestinal I/R was then induced in each rat by occlusion of the superior mesenteric artery (SMA) for 45 min via non-traumatic clamp, followed by re-perfusion for 120 min before the rats were euthanized and intestinal tissues recovered for analyses. Rats in the control I/R group showed a significant increase in intestinal malondialdehyde (MDA), NO, and TNFa contents, as well as increases in myeloperoxidase (MPO) enzyme activity, diffuse histological damage, and strong levels of Fas staining. Pre-treatment of rats with rosiglitazone resulted in a significant reduction in the intestinal MDA, NO, and TNFa contents and MPO enzyme activity associated with I/R; these rats also evidenced only mild histological damage and Fas staining. The protective effects of rosiglitazone were completely abolished by BADGE administration. Therefore, based on the results of this study, we conclude that the PPARg system plays an important role in intestinal I/R injury. We also note that free radicals (including NO), neutrophil infiltration, as well as select cytokines, are important mediators in I/R injuries. Key words: Ischemia/re-perfusion, peroxisome proliferator-activated receptor-g (PPARg), rosiglitazone, bisphenol A diglycidyl ether (BADGE), cytokines, nitric oxide.

The protective effect of rosiglitazone on renal injury of severe acute pancreatitis

Objective To investigate the effects of rosiglitazone, the agent of highly selective peroxisome proliferator-activated receptor-γ agonist, on the renal injury of rats with severe acute pancreatitis. Methods Fifty-four male Wistar rats were randomly (random number) divided into three groups : sham operation group ( SO group), severe acute pancreatitis group ( SAP group ) and rosiglitazone pretreatment group (ROSI group) . Severe acute pancreatitis model was induced by retrograde infusion of 5％ sodium taurocholate into the biliopancreatic duct. Rosiglitazone (6 mg/kg) dissolved in 10％ DMSO were injected into the femoral vein 30 minutes prior to the modeling. The solution of 10％ DMSO was given to rats of SO group and SAP group. Rats were sacrificed 3, 12 and 24 h after modeling. The levels of serum amylase, serum creatinine, urea nitrogen, urinary albumin, urinary lgG and αl-microglobulin were measured and analyzed statistically. Kidney tissue samples were stained respectively with hematoxylin and eosin for histopathological evaluation. Results The levels of serum amylase, serum creatinine, urea nitrogen, urinary albumin, urinary IgG and αl-microglobulin were significantly increased (P ＜ 0. 05 )after modeling, while lesser increases were found in ROSI group 12 h and 24 h after modeling (P ＜0. 05)compared with those in SAP group. Conclusions Renal injury can be induced by severe acute pancreatitis,while Rosiglitazone protects rats from renal injury in the setting of severe acute panereatitis. Key words: Rosiglitazone; Pancreatitis; Acute necrotizing; Renal injury; Animal experimentation; Peroxisome proliferators-activated receptor; Inflamation ; Protection

Protective Effects of Rosiglitazone on Retinal Neuronal Damage in Diabetic Rats

Purpose: To investigate whether rosiglitazone has a protective effect on retinal neural cells in diabetic rats, and to determine a possible anti-apoptotic mechanism.Methods: Streptozotocin-induced diabetic rats and control animals were randomized evenly to receive rosiglitazone or not, effects were examined after 24 weeks. Retinal histology was examined and quantified using light microscopy; Apoptosis of retinal neural cells was determined by terminal dUTP nick-end labeling assay; Retinal ultrastructure was examined by transmission electron microscopy; Proteins levels of cleaved caspase-3, signal transduction and activators of transcription-3 (STAT3), phospho-STAT3 (p-STAT3), and suppressors of cytokine signaling 3 (SOCS3) in the retinal tissues were also determined by western blotting.Results: Compared with the control group, the thickness of the overall retina, inner plexiform layer, inner nuclear layer reduced by 13.8%, 27.4% and 4.2%, respectively (p < 0.05) in the diabetic group after 24 weeks; The number of cells in the ganglion cell layer was also decreased by 18.6% (p < 0.05). There was apoptosis of retinal neurons in the diabetic rats. Diabetes also induced mitochondrial metamorphosis in ganglion cells and evident pyknosis in the outer nuclear layer. These effects were associated with increased levels of cleaved caspase-3, p-STAT3, and decreased levels of SOCS3. After treatment of rosiglitazone, the thickness of the retina and the number of cells in the ganglion cell layer were significantly greater than those in the diabetic group (p < 0.05). Rosiglitazone also attenuated the diabetic-induced apoptosis of retinal neurons and mitochondrial metamorphosis in ganglion cells. Consistent with these effects, rosiglitazone treatment also decreased cleaved caspase-3 and p-STAT3 expression and, at the same time, increased SOCS3 expression.Conclusions: Rosiglitazone attenuated diabetes-induced apoptosis in retinal neurons through activities that may involve inhibition of p-STAT3 by induction of SOCS3, which suggested that rosiglitazone might be used to prevent retinal neuronal damage in diabetes mellitus.

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Aldosterone (Aldo) causes podocyte damage by an unknown mechanism. We examined the role of mitochondrial dysfunction (MtD) in Aldo-treated podocytes in vitro and in vivo. Exposure of podocytes to Aldo reduced nephrin expression dose dependently, accompanied by increased production of reactive oxygen species (ROS). The ROS generation and podocyte damage were abolished by the mitochondrial (mt) respiratory chain complex I inhibitor rotenone. Pronounced MtD, including reduced mt membrane potential, ATP levels, and mtDNA copy number were seen in Aldo-treated podocytes and in the glomeruli of Aldo-infused mice. The mineralocorticoid receptor antagonist eplerenone significantly inhibited Aldo-induced MtD. The MtD was associated with higher levels of ROS, reduction in the activity of complexes I, III, and IV, and expression of the peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α and mt transcription factor A. Both the PPARγ agonist rosiglitazone and PPARγ overexpression protected against podocyte injury by preventing MtD and oxidative stress, as evidenced by reduced ROS production, by maintenance of mt morphology, by restoration of mtDNA copy number, by decrease in mt membrane potential loss, and by recovery of mt electron transport function. The protective effect of rosiglitazone was abrogated by the specific PPARγ small interference RNA, but not a control small interference RNA. We conclude that MtD is involved in Aldo-induced podocyte injury, and that the PPARγ agonist rosiglitazone may protect podocytes from this injury by improving mitochondrial function.

Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats.

BackgroundSirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ) on hepatic steatosis.MethodsTo investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg−1·day−1) by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes.ResultsRGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α) and Forkhead box O1 (Foxo1) in rat livers. AMP-activated protein kinase (AMPK) phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035), suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects.ConclusionOur results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.