| Background and Objective Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal failure in many developed and developing countries. The developmental and progressive mechanism of diabetic nephropathy include an activated rennin-angiotensin system (RAS), accumulation of advanced glycation end-products, an activated polyols pathway, oxidative stress and dyslipidaemia. The induction of cytokines such as transforming growth factorβ1 is also important. Connective tissue growth factor (CTGF) a downstream mediator of TGFβ,that is the most important pro-sclerosis growth factors. Diabetic nephropathy is generally considered a nonimmune disease; however, examination of human biopsies and animal models has shown the presence of accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines in diabetic kidneys. It was shown that treatment with angiotensin renin-angiotensin system (RAS) blockade as angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) or anti-inflammatory drugs as mycophenolate mofetil (MMF) and mizoribine attenuated renal injury in the diabetic rats. However, renal protection with either ACE inhibitor or MMF as monotherapy is suboptimal. We previously reported that the combination of enalapril (an ACE inhibitor) and MMF confers superiority over monotherapies on renoprotection. Our present study is to investigate whether RAS blockade combined with anti-inflammatory drugs have additional effects against the expression of CTGF in the kidney in diabetic rats. Methods Diabetes was induced by injection of streptozotocin after uninephrectomy. Rats were randomly separated into five groups: control (C), diabetes (DM), diabetes treated with enalapril (DM+E, an ACE inhibitor, 10 mg/kg/d by gastric gavage), diabetes treated with MMF (DM+MMF, 10mg/kg/d by gastric gavage), or diabetes treated with a combination of both agents (DM+E+MMF) and were followed for 8 weeks.24 h urinary albumin excretion rate (AER) and renal tissue morphology were observed by light microscopy after 8 weeks. Expression CTGF protein was performed by immunohistochemistry method in the kidney.Results 1.clinical and metabolic parameters: Rats in DM group had reduced body weight gain and increased blood glucose level. No effects on body weight and blood glucose were observed with monotherapy treatment or enalapril and MMF combination. Kidney enlargement was observed in DM group, which was significantly reduced by treatment with enalapril or MMF and further lowered by the combination of the two. 2. albumin excretion rate (AER):In DM group, albuminuria was significantly increased when compared to C group, treatment with enalapril or MMF attenuated the increase in albuminuria in the diabetic rats, but this level was still higher than that observed in control rats, the combination of enalapril and MMF was associated with a further reduction in albuminuria than was seen with either drug administrated alone, the similar AER level to that observed in control animals. 3.Renal histology: Rats in group DM had an increase in the glomerular volume when compared with the values in group C. Enalapril or MMF treatment ameliorated the increase of the glomerular volume, and the combination of the two was associated with further reduction in glomerular volume. Rats in group DM had an increase in the tubulointerstitial injury index when compared to group C, enalapril or MMF treatment was associated with a reduction in tubulointerstitial injury index as compared with group DM, but this did not reach statistical significance. The combination of the two was associated with a reduction in tubulointerstitial injury index as compared with group DM. 4.Renal CTGF expression: In the kidneys of group C, there was minimal staining for CTGF, diabetes was associated with a prominent increase in renal CTGF immunostaining, which was seen in glomeruli and tubulointerstitium, enalapril and MMF treatment reduced overexpression of CTGF in the glomeruli as well as in the tubulointerstitium, which nearly completely abrogated by combination therapy.Conclusion The combination of enalapril and MMF confers superiority over monotherapies on renoprotection, which mechanism may be at least partly correlated with synergetic suppression on overexpression of CTGF.
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