The Effect Of Atorvastatin On TGF-β₁ Expression In Diabetic Nephropathy And Its Effect Of Renoprotection

Objective: Diabetic nephropathy is a common complication of diabetic microvascular complications and a leading cause of end stage renal failure. Various mechanisms have been identified contributing to the development of diabetic nephropathy, such as heredity, hemodynamic factors, advanced glycation end products and many cell factors , especially transforming growth factor- β1(TGF- β1). Recently, a lot of researches have been done to intervene diabetic nephropathy by inhibiting TGF-β1. Current researches show that lipid-lowering drug, statins have renoprotective effect on diabetic nephropathy via downregulating TGF- β1 expression , thus providing a new project to prevent and treat diabetic nephropathy. In this study, atorvastatin was preventively applied to diabetic rats, aiming to observe its effect on serum cholesterol level, urinary excretion rate of albumin (Ualb) and a1-microglobulin(U a1-MG), intrarenal TGF-β1 expression and their interrelationships. The mechanism of renoprotective effect of atorvastatin on diabetic nephropathy related to TGF-β1 was specially studied.Methods: The rats were randomly divided into normal control rats (group NC), streptozotocin-induced diabetic rats (group DM) and diabetic rats treated with atorvastatin with 5mg/kg dosage every day (group DA). 8 Weeks later, Ualband Ua1-MG were measured by immunoradioassay as glomerular and tubular injury index respectively. Intrarenal TGF-β1 content and mRNA expression were measured by immunohistochemical technique and RT-PCR technique respectively. Pathological changes of renal tissue were observed under light microscopy and electron microscopy.Results: 1. 8 weeks later, the blood glucose levels of group DM and DA were similar (P>0.05), but much higher than that of group NC (P<0.01). 2. Serumcholesterol level, kidney atrophy index , creatinine clearance rate (Ccr), Ualb and Ua1-MG in group DA were lower than those in group DM (P<0.01, 0.01, 0.05, 0.05, 0.01 respectively). The above-mentioned data in group DM and DA were both higher than those in group NC (P<0.01). 3. Immunohistochemistry results show that both glomerular and tubular TGF-β1 chromaticity in group DA were higher comparing with group DM (P<0.01, 0.05 respectively). The TGF-β1 chromaticity in these two group were lower than that in group NC (P<0.01). 4. TGF-β1 mRNA expression in DA group were lower than that in group DM, both were higher than that of group NC. 5. 8 weeks later, it could be obviously observed under light microscopy and electron microscopy in group DM that glomerular volume increased and glomerular base membrane massively or localized thickend. These pathological changes in group DA were scarcely seen and less obvious than those in group DM. 5. Correlation analysis: Ualband Ua1-MG were positively correlated with Ccr(r=0.85, 0.87 respectively, P<0.01); serum cholesterol level was positively correlated with Ccr Ualb and Ua1-MG (r=0.74, 0.78, 0.75 respectively, P<0.01); Ualb was negatively correlated with glomerular TGF- P , chromaticity (r=-0.66, P<0.01); Ua1-MG was negatively correlated with tubular TGF- β1 chromaticity (r=-0.66, P<0.01); changes of serum cholesterol level has no correlation with changes of glomerular or tubular TGF-β1 chromaticity (r=-0.10,-0.17 respectively, P>0.05).Conclusions: 1.Glomerular and tubular TGF-β1 expression may increase in diabetic nephropathy, which contributing to the occurrence and developement of diabetic nephropathy. 2. Atorvastatin have renoprotective effect on diabetic nephropathy by suppressing TGF-β1 expression , which is independent of its lipid-lowering effect.