| Objective: Systemic lupus erythematosus (SLE) is a serious multi-system autoimmune disease characterized by the formation of antibodies. Lupus nephritis (LN) is one of the most important manifestation of SLE and is relevant to prognosis of SLE tightly. Research have showed that TGF-β1 (transform growth factor-β1) could aggravate glomerulosclerosis and renal interstitial fibrosis through enhancing mesangial cell and endotheliocyte proliferation and exacerbating extracellular matrix (ECM) synthesis and accumulation. Recent research suggested bone morphogenetic protein-7 (BMP-7) can reduce glomerulosclerosis and renal interstitial fibrosis through maintains epithelial cells phenotype, inhibit apoptosis of epithelial cells, activate degradation of extracellular matrix (ECM), decrease expression of proinflammatory cytokine, interfere with signal transduction pathway of TGF-β/Smads, and reverse effects of TGF-β1. Tripterygium glycosides (TG) is used for immune-associated disease such as rheumatism and nephrosis, but the toxic and side-effect of TG are apparent. The research of Action-Enhancing and Toxicity-Reducing effect on TG is necessary. Total glucosides of paeony (TGP) has favourable effects of anti-inflammatory, analgesia and immunoregulation, and satisfactory tolerance. In addition, TGP can amelioration various liver injurys obviously. The aim of this study based on murine model of chronic graft-versus-host disease(cGVHD) is to investgate the effect of BMP-7 on LN, the treatment mechanism of TG combine with TGP in LN and the action-enhancing and toxicity-reducing effect of TGP on TG through observe the effect of TGP combine with TG on the renal expression of BMP-7, renal function and hepatic function of cGVHD mice for the evidence of rational administration of TG and compatibility of effective component of the traditional Chinese medicine (TCM).Methods:(1) The murine LN model of cGVHD was employed, which was established by injecting with lymphocytes from female DBA/2 mice to Female (C57BL/6J×DBA/2) F1 (B6D2F1) hybrids aged 8-10 weeks intravenously 4 times at 3 days interval. The B6D2F1 hybrids were then randomly divided into lupus nephritis group, prednisone group, leflunomide group, TG group, TGP group, and TG+TGP group, with age-matched normal mice as the control group injected with physiological saline. (2) The medicines were given from the 9th week to the 12th week once a day. The general status of mice was observed before and after model and administration. After 4 weeks administration, 24hrs urinary protein excretion (UPE) and the levels of serum BUN, SCr, ALT, AST and liver tissue homo- genate SOD, MDA, GSH were detected. The pathologic change of kidneys of each group were observed by light microscope. The renal expression levels of BMP-7 and TGF-β1 were examined by immunohistochemical technique. (3) All statistical analyses of data were computed using Statistical Package for Social Sciences (version 13.0). Results are expressed as the mean±SD for the number of animals indicated. The sources of variation for multiple comparisons were assessed by one-way analysis of variance (ANOVA). Pearson correlation analysis was adopted. The differences were considered statistically significant at P<0.05.Results: (1) The levels of UPE, BUN and SCr of lupus nephritis group were increased significantly compared to control group (P<0.01). Compared with lupus nephritis group, the levels of UPE, BUN and SCr of prednisone group, leflunomide group, TG group, TGP group, and TG+TGP group were decreased notablely (P<0.05 or 0.01), and the TG+TGP group were the lowest (P<0.05 or 0.01). (2) The levels of ALT, AST of leflunomide group and TG group were increased significantly compared to control group and lupus nephritis group (P<0.01), and the levels of ALT, AST of TG+TGP group were decreased remarkably compared to TG group (P<0.01). (3) Compared with control group and lupus nephritis group, the levels of liver tissue homogenate SOD, GSH in the TG group were decreased significantly (P<0.05 or 0.01). The levels of liver tissue homogenate SOD, GSH in the TG+TGP group were signify- cantly higher than the TG group (P<0.01). Each group's MDA level was converse to SOD, GSH. (4) The pathology of kidney tissue was no changes in control group mice. There was glomerular mesangial proliferation, basilar membrane thickening, extracellular matrix expansion and interstitial cellular infiltration in lupus nephritis group. The kidney pathological changes were all alleviated in each treatment group, and there was significant difference between TG group and TG+TGP group. (5) The expression of BMP-7 in renal tubular epithelial cells and interstitial tissue was shown to be lower in the lupus nephritis group than in the control, though it was not found in renal glomerular cells. The levels of BMP-7 expression in each treatment group were increased obviously (P<0.05 or 0.01). The expression of BMP-7 was higher in TG+TGP group than TG group remarkably (P<0.01). (6) There was only little TGF-β1 expression in kidney tubules of control groups rats. The expression of TGF-β1 in mesangial cells, renal tubular epithelial cells, vascular endothelial cells, and inflammatory cells was shown to be higher in the lupus nephritis group than in the control group (P<0.01). The levels of TGF-β1 expression in each treatment group were decreased obviously (P<0.05 or 0.01). The difference of kidney TGF-β1 expression between TG+TGP group and TG group was noticeable (P<0.05). (7) The levels of UPE,BUN,SCr were relevant to BMP-7 expression in kidney negatively (r=-0.814, -0.555, -0.766 respectively, all P<0.01) and TGF-β1 positively (r=0.800, 0.684, 0.740 respectively, all P < 0.01). (8) The correlation coefficient between the level of BMP-7 and TGF-β1 expression in kdney of mice was -0.665 (P<0.01).Conclusions:(1) BMP-7 is an important cytokine to protect renal function, and has adverse effect to TGF-β1. The down-regulation of BMP-7 is suggested to be related to developing and progress of lupus nephritis. (2) Tripterygium glycosides and tripterygium glycosides combined with total glucosides of paeony have prominent therapeutic effect on cGVHD lupus-like mice. The renoprotective effect of tripterygium glycosides and tripterygium glycosides combined with total glucosides of paeony maybe through up-regulation of BMP-7 and down-regulation of TGF-β1. (3) The therapeutical effect on UPE, BUN, Scr, BMP-7 and TGF-β1 in cGVHD lupus nephritis mice of tripterygium glycosides combined with total glucosides of paeony is better than tripterygium glycosides alone, which suggested that tripterygium glycosides and total glucosides of paeony have synergistic effect. (4) Tripterygium glycosides has noticeable hepatotoxicity, which is related to oxidative damage, and total glucosides of paeony has hepatoprotective effect, which is related to anti-oxidation.(5) Compatibility of tripterygium glycosides and total glucosides of paeony has action-enhancing and toxicity-reducing effect to cGVHD lupus-like mice, which suggest that the medication model of the effective component of the traditional Chinese medicine (TCM) provide a significant information for moderni- zation of TCM.
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