| With the development of social development and change in lifestyle,the incidence of diabetes mellitus(DM)is increasing over years.To date,DM has been the third most common most common non-communicable lifestyle disease world wide following cancer and cardiovascular diseases and has become an important health problem.Diabetic nephropathy(DN)was first proposed by ConLunnius(1764)and Rolls(1798),DN has been one of major complications of DM and one of important causes of disability and mortality.DN refers to the renal injury secondary to microvascular disease of the kidney in DM patients.Clinically,DN is characterized by persistent proteinurin.Pathologically,DN is characterized by acellular mesangial area widening or nodular lesions and thickening of glomerular capillary basement membrane.In recent years,the incidence of DN is increasing with the increase in the incidence of DM.In Western countries,DN has been a major cause of chronic renal failure.In 1997,DN accounted for 44%of the newly diagnosed end stage kidney disease(ESRD)(80%was caused by type 2 DM);,in Japan,DN accounted from 28%of ESRD;In Chinese Hongkong and Taiwan,DN accounted for more than 20%of ESRD;In China mainland,DN accounted for 5%?10%of ESRD.Moreover,in China,the prevalence of DN is increasing and patients with DN increasingly become younger in recent years.Currently,the pathogenesis of DN is still poorly understood.Long term high blood glucose,high glycation end products,increased polyol pathway activity,increased protein kinase C,increased intraglomerular pressure,changes in multiple cytokines and growth factors and genetic factors have been confirmed to play important roles in the pathogenesis of DN.In recent years,some studies have indicated that oxidative stress and inflammation play crucial roles in the pathogenesis of DN.Currently,favorable control of blood glucose,lipids and blood pressure,change in life style,and application of angiotensin converting enzyme inhibitors/angiotensin receptor antagonists(ACEI/ARB)have been used as the main strategies for the treatment of DN,but the efficacy is still limited.Thus,it is imperative to develop new strategies for the treatment of DN in DM patients and to delay the progression of DN into ESRD.Dihydromyricetin(also known as ampelopsin)is a flavonoid isolated from Ampelopsis grossedentata.Traditionally,Ampelopsis grossedentata is used as tea in Yao people in China to treat pyretic fever and cough,pain in pharynx and larynx,and jaundice hepatitis.It is also used in nephritis,hepatitis,halitosis,and polyorexia prevention and treatment.Dihydromyricetin is the richest component found in Ampelopsis grossedentata.In recent years,studies have demonstrated that dihydromyricetin shows multiple activities,including anti-oxidative,anti-inflammatory,anticancer,antimicrobial,cell death-mediating,and lipid and glucose-metabolism-regulatory activities.This study aimed to investigate the nephroprotective effects of dihydromyricetin on DN in DM rats and explore whether the nephroprotective effects of dihydromyricetin were related to its anti-oxidative and anti-inflammatory activities.Our findings may provide experimental evidence for the prevention and treatment of DN.Objectives1.Construction of renal injury model in DM rats;2.Evaluation of nephroprotective effects of dihydromyricetin on renal injury in DM rats.3.Assessment of oxidative stress and inflammation in the kidney of DM rats with renal injury after dihydromyricetin treatment.Materials and methods1.Sprague Dawley(SD)rats were fed with high fat diet for consecutive 8 weeks,and then were intraperitoneally injected with 35 mg/kg streptozotocin.3 days later,the fasting blood glucose(FBG)was detected for the assessment of DM model.2.DM rats were randomly assigned into model group(B group),160 mg/kg'DHM group(C group),320 mg/kg' DHM group(D group)and 480 mg/kg' DHM group(E group).DHM was intragastrically administered once daily for consecutive 16 weeks.3.At 0,8,12,16,20 and 24 weeks after the initiation of this study,rats were fasted,and FBG was detected via tail vein.At the end of whole study(after 16-week treatment),rats were anesthetized and sacrificed.The blood was harvested for the detection of blood lipids and kidney function.The kidney was collected for the pathological examination after HE staining and as well as detection of oxidative stress markers and inflammation markers.Results1.After high fat diet treatment,intraperitoneal injection of streptozotocin was successfully induce DM in rats which were characterized by significant and sustained high FBG.In addition,renal pathology showed the glomeruli and renal tubules were normal,and there were no tubular dilation,interstitial infiltration of inflammatory cells and fibrous tissue hyperplasia in the kidney of control rats.In DM rats,the glomeruli were enlarged,some of them showed nodular glomerulosclerosis,even some Kimmelstiel-Wilson nodules were noted,the renal tubules showed patchy atrophy and compensatory dilation.Moreover,the blood lipids in DM rats increased significantly and the kidney function was markedly compromised in DM rats as compared to rats in control group.These findings suggest that the DM induced renal injury model was successfully established in this study.2.After treatment with dihydromyricetin at different doses,the blood glucose in DM rats increased significantly as compared to untreated rats although it was still than in normal level.In addition.the blood lipids reduced dramatically and the kidney function was remarkably improved after dihydromyricetin treatment as compared to untreated rats.Of note,the reductions in blood glucose and blood lipids as well as the improvement of kidney function seemed to be related to the dose of dihydromyricetin:the blood glucose and lipids reduced and the kidney function was improved with the increase in the dose of dihydromyricetin.These findings indicate that dihydromyricetin may regulate the blood glucose and lipids to exert nephroprotective effects on the renal injury in DM rats,and the nephroprotective effects are better after treatment with dihydromyricetin at intermediate or high dose.3.At the end of study,the markers of oxidative stress and inflammation increased dramatically in the kidney of DM rats,the protein expression of nuclear Nrf2,HO-1 and 1?B? reduced markedly,but the NF-?B expression increased significantly in the kidney of DM rats as compared to control rats.After treatment with dihydromyricetin at different doses,markers of oxidative stress and inflammation reduced markedly in the kidney of DM rats,which was accompanied by the significant increase in the protein expression of uclear Nrf2,HO-1 and I?B? and marked reduction in NF-?B expression in the kidney of DM rats as compared to untreated rats.These findings suggest that dihydromyricetin may exert nephroprotective effects via inhibiting oxidative stress sand inflammation in the kidney of DM rats.Conclusion1.Intraperitoneal injection of 160 mg/kg,320 mg/kg and 480 mg/kg dihydromyricetin is able to improve the blood glucose,lipids and kidney function of DM rats and exert nephroprotective effects,which are better after treatment with dihydromyricetin at intermediate or high dose.2.The nephroprotective effects of dihydromyricetin in DM rats may be related to its anti-oxidative and anti-inflammatory activities. |
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