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Aim To evaluate the reno-proteetion of saxagliptin combined with metformin in mice with T2DM anrl its relationship with redox balance.Meth¬ods C57BL/6J mice were fed with high fat diet and injected with low dose STZ intraperitoneally to establish T2DM mouse model.Then they were randomly divided into T2DM group, glibenclamide group ( Gli group), metformin group ( Met group) , saxagliptin group ( Sax group) and saxagliptin + metformin group ( S + M group) , and normal control group ( NC group) with 8 mice in each group.Eight weeks after intervention the mice were weighed.Blood, urine and renal tissue sam¬ples were collected to measure GHbA,c, FBG, Alb, 8-OHdG, 8-iso-PG, SOD, GSH, GSSG and Ucr.The pathological morphology of renal tissues in each group was observed.Results Saxagliptin combined with metformin reduced significantly the levels of Alb/Ucr ( UACR) , 8-0HdG/Ucr( UOCR) , 8-iso-PG/Ucr( UP- CR) , increased the activity of SOD and GSH/GSSG ratio, and improved the pathological changes of renal tissues, which were superior to those in Met group and Sax group.Conclusions Saxagliptin combined with metformin have a synergistic protective effect on the kidneys of type 2 diabetic mice.The mechanism is partly related to alleviating oxidative stress and impro¬ving redox balance in vivo.
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Aim To observe the effects of metformin (MET) on the silencing regulatory protein 1 (SIRT1) mRNA and protein expression in renal tissues of type 2 diabetic mellitus (T2DM) rats, and explore its reno-protective mechanisms. Methods Thirty model T2DM rats were randomly divided to glibenclamide in-tervention group (GLY group, 5 mg·kg-1·d-1), metformin intervention group (MET group,300 mg· kg-1· d-1) and diabetic control group (T2DM group),and 10 rats with normal glucose tolerance were used as normal control(NC group). After 8 weeks, HbA1c,blood glucose (BG), urea nitrogen (BUN), urinary albumin, creatinine and glomerular basement membrane thickness (GBMT) were detected. The ex-pression of SIRT1 protein in renal tissues was detected by immunohistochemistry, the expression of SIRT1 mRNA in renal tissues was detected by real-time PCR, and urinary SIRT1 protein was detected by ELISA. Results At the end of 8 weeks, the levels of BG,HbA1c,urinary albumin/urinary creatinine(UACR), urinary SIRT1/urinary creatinine (USIR) and GBMT in MET and GLY groups were significantly lower than those in T2DM group (P<0.05). There was no sig-nificant difference in BG, HbA1c and GBMT between MET group and GLY group (P>0.05). The expres-sions of SIRT1 mRNA and protein in MET group were significantly lower than those in NC group (P <0.05), but higher than those in T2DM group (P <0.05). The UACR, expression of SIRT1of renal tis-sues in MET group was higher than that in GLY group (P<0.05),but urinary SIRT1 protein was lower than that in GLY group (P <0.05). Conclusion Met-formin can increase the expressions of SIRT1 in renal tissues of T2DM rats,which may be related to its renal protection.
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<p><b>BACKGROUND</b>Oxidative Stress and p38 mitogen-activated protein kinase (p38MAPK) play a vital role in renal fibrosis. Pioglitazone can protect kidney but the underlying mechanisms are less clear. The purpose of this study was to investigate the effect of pioglitazone on oxidative stress and whether the severity of oxidative stress was associated with the phosphorylation level of p38MAPK.</p><p><b>METHODS</b>Rat mesangial cells were cultured and randomly assigned to control group, high glucose group and pioglitazone group. After 48-hour exposure, the supernatants and cells were collected. The protein levels of p22(phox), p47(phox), phosphorylated p38MAPK, total p38MAPK were measured by Western blotting. The gene expressions of p22(phox), p47(phox) were detected by RT-PCR. The levels of intracellular reactive oxygen species (ROS) were determined by flow cytometry. The levels of superoxide dismutase (SOD) and maleic dialdehyde (MDA) in the supernatant were determined respectively.</p><p><b>RESULTS</b>Compared with the control group, the expression levels of p22(phox), p47(phox), phospho-p38 and ROS significantly increased, activity of SOD decreased in high glucose group, while the level of MDA greatly increased (P < 0.01). Pioglitazone significantly suppressed p22(phox), p47(phox) expressions and oxidative stress induced by high glucose. The expressions of p22(phox), p47(phox), phospho-p38MAPK and ROS generation were markedly reduced after pioglitazone treatment (P < 0.05). The activity of SOD in the the supernatant increased (P < 0.05), while the level of MDA decreased greatly by pioglitazone (P < 0.05). The level of oxidative stress was associated with the phosphorylation level of p38MAPK (P < 0.01).</p><p><b>CONCLUSION</b>Pioglitazone can inhibit oxidative stress through suppressing NADPH oxidase expression and p38MAPK phosphorylation.</p>