The Effect of Leflunomide on Renal Expression of GLUT-1 mRNA and the Extracellular Matrix in Diabetic Rats

Objective:To investigate the effects of Leflunomide on the expression of glucose transporter-1(GLUT-1)mRNA and the extracellular matrix in the diabetic rats,and probe into its mechanism.Methods:An animal model of diabetes was established by intraperitoneal injection of STZ.Rats were randomly divided into normal control group(group A),diabetic control group(group B)and Leflunomide treated group(group C).Four rats of each group were randomly chosen to be sacrificed at the end of the 4th、the 8th and the 12th week.Samples were then collected,including body weighting,right kidney weight,blood sugar,serum creatinine,blood urea nitrogen,cholesterol,triglyceride,24-hour urinary protein excretion.Renal GLUT-1 mRNA expression was measured with reverse transcriptase-polymerase chain reaction(RT-PCR).Renal pathomorphology was observed by HE and PAS staining.Laminin and type Ⅳ collagen were measured with immunohistochemical techniques.Results:(1)Compared with Group A,Blood sugar was increased significantly(P0.01)in Group B but 24-hour urinary protein excretion did not increased significantly(P0.05)at the incipient time when the animal model of diabetes was established successfully.At the end of the 4th week,body weight was decreased significantly(P0.01)while the kidney weight index,serum creatinine,blood urea nitrogen,cholesterol,triglyceride,24-hour urinary protein excretion and renal GLUT-1 mRNA expression were increased significantly(P0.01).At the end of the 12th week,renal GLUT-1 mRNA expression,the kidney weight index,serum creatinine of group C were not increased significantly(P0.05).(2)Compared with Group B,serum creatinine,and blood urea nitrogen were decreased(P0.05)at the end of the 8th week.Cholesterol,24-hour urinary protein excretion and renal GLUT-1 mRNA expression were decreased significantly(P0.01).At the end of the 12th week,body weight was increased(P0.05),the kidney weight index and triglyceride were decreased significantly(P0.01).HE and PAS stain showed diffused glomcrulus hypertrophia,mesangial cell proliferation and mesangial matrix or nodular multiplication and thickened glomerular and tubular basement membrane of rats in Group B.In Group C these changes alleviated.With immunohistochemical(IHC)analysis,the expression of Laminin and type Ⅳcollagen were faintly observed in non-diabetic glomeruli;diabetic rats revealed enhanced expression of Laminin and type Ⅳcollagen in glomeruli;Leflunomide treated diabetic rats revealed the decreased expression of Laminin and type Ⅳ collagen in glomeruli.Conclusion:Leflunomide can decrease the 24-hour urinary protein excretion and correct the lipid metabolism disorder of the diabetic rats and inhibit renal hypertrophy and fibrosis hardening.The mechanism might be related with that Leflunomide can down-regulate the synthesis and activity of GLUT-1 mRNA.