Effects Of Mycophenolate Mofetil On Renal Tubular Epithelial Cells Transdifferentiation In Diabetic Rats

Background and Objective:In recent years, studies have shown that the immunosuppressant mycophenolate mofetil (mycophenolate mofetil, MMF) has a protective effect in experimental diabetic nephropathy (diadetic nephropathy, DN), the mechanism may relate with inhibiting the renal inflammatory cell infiltration. However, whether mycophenolate mofetil can inhibit renal tubular epithelial cells transdifferentiation in diabetic nephropathy, there is no related reports currently. In this study, we established streptozotocia(STZ)-induced diabetic rats model, and treated with mycophenolate mofetil, to observe its effects on general states, each hematuria indicator, the pathological morphology change of renal tubulo-interstitium and the expressions of a-smooth muscle actin(a-SMA) and transforming growth factor-beta1(TGF-β1) in renal tissues of diabetic rats, to investigate the effects and possible mechanism of mycophenolate mofetil(MMF) on renal tubular epithelial cells transdifferentiation in diabetic rats, and we hope it may provide a new theoretical basis for elucidating the protection mechanism of mycophenolate mofetil in diabetic nephropathy.Methods:There were thirty four healthy male SD rats in thist study, after one week adaptation feeding, eight rats were randomly selected as a normal control group (group N) and the rest twenty six rats were induced to the diabetes models by a single intraperitoneal streptozotocia injection with the dose of60mg/kg, and the rats in group N were injected with equivalent sodium citrate buffer solution. And then the successful modeling rats injected with STZ were randomly divided into diabetes mellitus group (group DM),and diabetes mellitus treated with MMF group(group M),12rats in each group. Replication model successfully for four weeks later, the rats in group M were given drugs by gavage once a day for8weeks, according to the dose: mycophenolate mofetil lOmg/kg/d, while the rats in group N and group DM were given distilled water with equal volume by gavage at the same time.12weeks later, we measured blood glucose, body weight, kidney weight kidney weight/body weight,24h urinary protein, serum creatinine and blood urea nitrogen of all rats and observed the pathological morphology change of renal tubulo-interstitium. Immunohistochemistry staining and Western Blot were conducted to detect expression of a-SMA and TGF-β1in renal tissues.Results:(1) General states changes of rats in each group:The levels of blood glucose, kidney weight, kidney weight/body weight,24h urinary protein, serum creatinine and blood urea nitrogen were significantly higher in group DM and group M than those in group N (P<0.01), and body weight was significantly lower (P<0.01). All the above parameters were significantly decreased in group M compared with group DM(P <0.01), except for the level of blood glucose, body weight(P>0.05).(2) Pathological morphology changes of rat renal tubulo-interstitium in each group:The kidney structure of group N was clear, and there were no tubulo-interstitial lesions. While in group DM, there were pathological changes of diabetic renal tubulo-interstitium, renal tubular epithelial cells granulovacuolar degeneration, tubule expansioned remarkably, basement membrane thickened,inflammatory cells infiltrated, collagen fibers increased.Compared with group DM, the lesions were significantly reduced in group M. Statistical analysis showed that tubulo-interstitium damage index(TII) in group DM and group M was significantly higher than it in group N (P<0.01), TII in group M significantly lower than it in group DM (P<0.01). (3) Immunohistochemistry results:Expressions of a-SMA and TGF-β1in renal tubular cells were comparatively higher in group DM and group M than those in the group N(P<0.01), but those in the group M were significantly lower than those in the group DM(P<0.01).(4) Western blot results:Expressions of a-SMA and TGF-β1in renal tissue of the group DM increased by3.4and1.1.times compared with those of the group N, and reduced by55%and40%in the group M separatively(P<0.01). serum creatinine,Conclusion:MMF can significantly lower kidney weight, kidney weight/body weight,24h urinary protein, serum creatinine and blood urea nitrogen, improve tubulointerstitial injury of diabetic nephropathy. The mechanism of its protective effect may be it can down-regulate the expression of a-SMA and TGF-β1in diabetic renal tubular epitheliar cells, inhibit renal tubular epithelial cells transdifferentiation, and delay the process of diabetic renal interstitial fibrosis.