| Aims:This study aims to investigate the protective effects of GLP-1analogueExenatide on the kidneys of type-2diabetes rats.Methods:Male SD rats of eight weeks were randomly into NC group, DM group andEX+DM group. Diabetes was induced by intraperitoneal administration of30mg/kgof STZ after4weeks of high fat and high glucose diet. NC group received acorresponding amount of citrate buffer only. EX+DM rats received subcutaneousadministration of Exenatide (3μg/kg, twice a day) for eight weeks. At the end of theexperiment, blood glucose, HbA1c, serum lipids, creatinine (CREA), blood ureanitrogen (BUN) and24hour urine micro-albumin (24h UMA) were measured.Furthermore, the flow-pressure relationships were determined for maximallyvasodilated perfusion kidneys in vivo. The morphological changes of renal tissueswere observed under the light and electron microscope. Real-time fluorescencequantitative PCR (QRT-PCR) was used to examine the mRNA levels of TGF-β1transforming growth factor-β1(TGF-β1), fibronectin1(FN1), connective tissuegrowth factor (CTGF) in renal tissues. MDA content and SOD activity were measuredby ELISA kits. AGEs, RAGE and GLO-1were also detected at the end of theexperiment.Results:1. Diabetic rats exhibited dramatically increased blood glucose (24.3+1.9mol/l)、HbA1c (2.56+1.98g/ml)、food intake (37.7+2.1g)、water intake (37.7+2.1g)throughout the entire period of the experiment, compared with those of NC rats(5.0+0.4mol/l;0.39+0.77g/ml;20.5+1.7g;27.1+0.4ml respectively)(P<0.001).However, treated with Exenatide markedly ameliorated the above abnormalities(19.4+2.1mol/l；2.11+0.34g/ml;31.8+3.8g;104.4+15.6ml respectively)(P<0.001),compared with that of DM group. 2．There were no significant differences in serum BUN and CREA between the NC,DM, and EX+DM group (54.2+12.0mmol/l;60.1+10.8mmol/l;50.5+16.0mmol/lrespectively for BUN;7.1+1.2umol/l;8.3+2.6umol/l;8.31+2.92umol/l respectivelyfor CREA)(P>0.05). However, renal index (renal weight/body weight*1000) and24hUMA were markedly increased in DM rats (6.0+0.8;564.2+125.6mg respectively),compared with that of NC rats (3.0+0.3;74.7+9.3mg respectively)(P<0.001). Incontrast, renal index and24h UMA were dramatically decreased in diabetic ratstreated with Exenatide, compared with those of untreated DM group (P<0.001).3. There were significant linear relationship between the inflow rate and the arterialdistending pressure under the regression analysis. Pearson correlation coefficients (r2)for every individual ranged from0.01to0.99. The slope of the flow-pressurerelationship was steeper in DM rats than NC rats (P<0.01), while in EX+DM rats, theslope was significantly lower than that of DM group (P<0.01).4. The DM rats exhibited glomerular basement membrane thickening, mesangial cellproliferation, mesangial matrix increases and renal interstitial inflammatory cellinfiltration. The above-mentioned renal morphological changes had someimprovement in the EX+DM rats, compared with the DM group.5. The expression of TGF-β1、FN1、CTGF in renal tissues measured by QRT-PCR wasup-regulated in DM rats (P<0.05), compared with those of NC rats; while in EX+DMrats, the expression was down-regulated (P<0.05).6. Diabetic rats had a profoundly decrease in serum and renal SOD activity(91.9+18.0U/ml;106.0+30.5U/mgprot respectively) than that was seen in NC rats(118.1+15.5U/ml;269.8+47.1U/mgprot respectively)(P<0.01). Exenatide-treatedrats increased the SOD activity in serum and renal samples (118.6+17.1U/ml;202.5+29.6U/mgprot respectively)(P<0.05). Diabetic rats had a larger increase inserum and renal MDA content (10.5+0.7nmol/ml;1.2+0.4nmol/mgprot respectively)than that was seen in NC rats (9.1+0.9nmol/ml;0.6+0.2nmol/mgprot respectively)(P<0.01). Exenatide-treated rats decreased the MDA content in serum and renalsamples (9.5+0.5nmol/ml;0.7+0.2nmol/mgprot respectively)(P<0.05). 7. Diabetes markedly elevated AGEs in serum and renal tissues and RAGE in serum(26.4+2.5ng/ml;281.5+4.7pg/ml;4.6+0.2ng/ml respectively), compared with thoseof NC rats (15.0+0.1ng/ml;252.2+2.7pg/ml;3.1+0.2ng/ml respectively)(P<0.01);whereas rats treated with Exenatide exhibited dramatically decrease (15.4+0.2ng/ml;252+7.0pg/ml;3.0+0.2ng/ml respectively), compared with those of DM rats(P<0.001). Diabetes decreased serum GLO-1(7.0+0.6ng/ml), GLO-1gene andprotein in renal tissues (P<0.05), compared with those of NC rats (8.6+0.3ng/ml);while rats treated with Exenatide had a significantly increase (16.1+1.5ng/ml),compared with those of DM rats (P<0.01).8. The renal expression of ERK1/2gene and protein in the DM rats were much higherthan those in the NC rats (P<0.05); however, Exenatide had significantly reduced theexpression of ERK1/2, compared with those in DM rats (P<0.05).Conclusions:Generally speaking, GLP-1analogue Exenatide may be have protective effects on thekidneys of type-2diabetic rats. These effects are closely associated with thesuppression of AGEs, RAGE expression and the alleviation of oxidative stress. Thisstudy indicates that Exenatide may be an effective therapeutic for the treatment ofdiabetes-related nephropathy. |
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