| BACKGROUND: The current therapy for chronic proteinuric nephropathies is angiotensin-converting enzyme inhibitors (ACEi), which slow, but may not halt, the progression of　the disease, and which may be not effective to the same degree in all patients. The great importance of HMGCoA reductase inhibitors (statins) in treatment of hyperlipidemia is well known, and accepted. Numerous multicenter trials have shown the effectiveness of statins in lowering cholesterol concentration, slowing down progression of atherosclerosis, and in decreasing number of cardio-vascular events. However, since the discovery of statins experiments have been carried out showing other mechanisms of action of these drugs. Many circumstances expose the antiproliferative, and antiinflammatory influence of statins. This study investigated the possible mechanism of combining use of ACEi with statin to ameliorate renal injury in nitric oxide(NO) difecient rats with renal lesions. METHODS: 56 SD rats were devided into two groups randomly: Control group,( O group, n=16); L group, L-NAME 50mg/kg.d-1 .After 4 weeks,8 rats from each of 2groups were sacrificed.Since the 5th week,the rats of L group were devided into 4 groups of 8rats each: L group, L-NAME 50mg/kg.d-1 ;S group, L-NAME 50mg/kg.d-1+ Fluvastatin 5mg/kg.d-1;C group,L-NAME 50mg/kg.d-1+ Captopril 5mg/kg.d-1; S+C group , L-NAME 50mg/kg.d-1+ Fluvastatin 5mg/kg.d-1+ Captopril 5mg/kg.d-1 .Systolic blood pressure was measured with tail-cuff method every two weeks.Urinary albumin(UAlb),N-acetyl-beta-D-glucosamindase(NAG) andβ2-microglobulin protein(Uβ2-M) were measured at each study point. Rats were sacrificed after another 8 weeks. The level of serum triglyceride, total cholesterol and Cr, plasma and renal tissue NOx-, angiotensinⅡ(AngⅡ) were measured. Kidney histopathologic abnormality were examined by general and electronic microscope. The level of transforming growth factorβ1(TGF-β1) ,collagen-I,collagen-IV and fibronectin(FN) in the renal cortical were measured with Western blotting. RESULTS: Blood pressure began to climb up since the second week in L group, and reached the highest point at week 12. Fluvastatin had little effect on the level of blood lipid and blood pressure .Captopril lowed blood pessure significantly with no effect on blood lipid.Ualb, Compared with O group,UNAG and Uβ2-M increased rapidly and steadily and reached the peak at week 12 in L group. UAlb was 62.0±12.8mg/L vs 26.4±6.80mg/L (P<0.001). NAG was 148.4±26.5mg/L vs 118.6±12.8mg/L(P<0.01).Uβ2-M was 0.126±0.032mg/L vs 0.075±0.015 mg/L. (P<0.001). lomerular filtration membance was impaired , glomerulosclerosis and tubulointerstitial fibrosis was developed initially in L group after 4 weeks. The level of plasma and renal tissue NO was decreased and the level of plasma and renal tissue AngⅡ were increased initially in L group after 4 weeks too. TGF-β1 , collage-I,collage-IV and FN in renal cortical were over-expressed initially at the same time.The renal impairment and the changes in plasma and renal tissiue became more obvious and severe at the end of the experiment. Ualb,NAG and Uβ2-M decreased stablely since the 5th week in S,C and S+C group,especially in the S+C group, compared with L group.Fluvastatin and captopril ameliorated the renal injury in the way of inhibiting the degree of glomerulosclerosis and tubulointerstitial fibrosis. The number of cell and accumulation of ECM in the glomerular was much less in S group,C group and S+C group,especially in S+C group.While increasing the level of NO in plasma and cortical,fluvastatin and captopril decreased the level of AngⅡin plasma and cortical significantly, especially in S+C group. The expression of TGF-β1, collagen-I,collagen-IV and FN in renal cortical were depressed remarkblely in S group,C group and S+C group,especially in S+C group. CONCLUSION: Ualb,UNAG and Uβ2-M can reflect the renal injury at the early stage in the NO-deficient rats. UNAG seems to have more sensitivity. Since 4 week,the glomerulosclerosis and tubulointe... |
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