| Background: The diabetic nephropathy (DN) is one of the most important causes of chronic renal failure and end stage renal disease (ESRD) in the world. It is also one of the most significant long-term complications in diabetic patients. About 40% of people with insulin-dependent diabetes will eventually develop end-stage renal disease. At least 20% of people with NIDDM will develop diabetic nephropathy. ~[1] In our country, with the increasing number of the diabetic patients and the prolonging of the live time, DN has become the major cause of the ESRD compared to its third place before.There is growing evidence that tubular injury is a major feature in the development of renal dysfunction in type 2 diabetes ~[2-4] . Tubular cells are are not only affected secondary to glomerular injury but are also primary targets for pathological influences in diabetes ~[5-9]. Typical glomerulopathy is present in only one-third of type 2 diabetic patients with microalbuminuria, while another third demonstrates normal renal structure. The last one-third has no or absent glomerular changes but disproportional severe tubulointerstitial lesions~[10].Proteinuria, especially albuminuria, is always recongnized as the signal of the renal and some cardial vascular diseases[11]. While microalbuminuria is a diagnostic evidence of the early stage of the diabetic nephropathy. Early detection, prevention and treatment of the microalbuminuria has the important significance to delaying the injure of the renal function. The reabsorption of albumin in the proximal tubule is a endocytic pathway involved the highly activated receptor-medicatde megalin/cubilin complex[12].This complex contains megalin/cubilin receptor, NHE3, vacular H-ATPase , Cl channel , C1C-5 and interaction with the actin cytoskeleton[13].Some evidence shows the microalbuminuria in the early stage of the diabetic nephropathy has the close relationship with the defect and abnormal function of the megalin'14^.However, there has no report about the expression of cubilin in the early stage of the diabetic nephropathy still now. Objective: (1) To observe the expression of the cubilin in the tubules of STZ-induced diabetic nephropathy rats, and its relation to the albuminuria, furthermore to investigate the mechanisms of the tubular dysfunction in the early stage of the diabetic nephropathy.(2) To observe whether the irbesartan, monopril and shiye have the effects on the expression of the cubilin in the tubules of STZ-induced diabetic rats, and to investigate their new target in the treatment of the diabetic nephropathy..Method: (1): Sprague-Dalwley (SD) rats were randomly divided into two groups: normal control, diabetic nephropathy. Diabetes was induced by injection of STZ ip. The 5 rats of the two groups were sacrificed at week 2,4, and 6 respectively, meanwhile blood glucose, body weight, kidneyweight,24-hours " albuminuria, 24-hours urine volume,24-hours urine creatinine concentration, serum creatinine and urea nitrogen were observed in the rats at week 2,4,and 6 respectively. After that, we calculated the creatinine clearance and renal hypertrophy index. The renal expression of cubilin in two groups were determined by immunohistochemistry and RT-PCR at week 2,4, and 6 respectively.(2) : Sprague-Dalwley (SD) rats were randomly divided into five groups: normal control, diabetic nephropathy, diabetic nephropathy treated with Irb(50mg/kg),diabetic nephropathy treated with mono(10mg/kg) and diabetic nephropathy treated with shiye(10ml/kg). Diabetes was induced by injection of STZ ip. Blood glucose, body weight, 24-hours albuminuria, 24-hours urine volume, 24-hours urine creatinine concentration, serum creatinine and urea nitrogen were observed in the rats at week 2, 4, and 6 respectively, then calculated the creatinine clearance. The 5 rats of the five groups were sacrificed at week 6, measured the kidney weight and calculated the creatinine clearance and renal hypertrophy index. The renal expression of CTGF and a -SMA in five groups were determined by immunohistochemistry at week 6, meanwhile the renal expression of cubilin in five groups were determined by immunohistochemistry and RT-PCR at week 6.Results: (1) the expression of cubilin in DN group is significant decreased at week 2(P<0.05), and the expression of cubilin continues to decrease from week 2 to week 6.Also there is significant difference between each two time point(P<0.05), and the attitude of the decrease of the cubilin is a?t completely pe^itively correlated with the attitude of the increase of thealbuminuria.(2) In all the groups, the expression of cubilin in N group is the highest, the DN group is the lowest, and the DN-A and DN-M groups is significant higher than N group (P<0.05), but there is no significant difference between the DN-A and DN-M groups (P>0.05). The expression of the cubilin in DN-S group is a little bit higher than the DN group, but there is no significant difference (PXX05). The expression of CTGF and a -SMA in DN-A, DN-M and DN-S groups are higher than the DN group, and the first two groups have the significant difference with the DN group (P<0.05), but the DN-S group has not P>0.05). At week 6,the 24-hour albuminuria, serum creatinine and urea nitrogen, kidney hypertrophy index of all the three treated groups were decrease, and the DN-A and DN-M groups has the significant difference with the N group (PO.05), but DN-S group has not (P>0.05). Conclusion: (1) the expression of cubilin in early stage of the diabetic nephropathy (at week 2) is significantly decreased, it contributes to the development of the microalbuminuria, with the time goes on, the expression of cubilin continues to decrease, but the attitude of the decrease is eet completely passively correlated with the attitude of the increase of the 24-hour albuminuria.(2) monopril and irbesartan can even increae the expression of cubilin in the early stage of the diabetic nephropathy, decrese the CTGF and a -SMA, and also it can prevent the increase of the 24-hour urine volume, 24-hour albuminuria, serum creatinine and urea nitrogen, and prevent the renal hypertrophy; therefore shiye has some effects in these areas, it has no significant difference with the DN group.
|
PDF Full Text Request