肾素—血管紧张素系统在慢性环孢素肾病中的作用

Role of RAS in kidney transplantation patients with CsA-induced chronic nephropathy

目的测定肾素、血管紧张素Ⅱ(AngⅡ)在慢性环孢素(CsA)肾病肾移植患者肾组织、血浆中的水平,探讨肾素-血管紧张素系统(RAS)在慢性CsA肾病中的作用。方法 (1) 采用免疫组化、放射免疫和荧光偏振法,测定13例慢性CsA肾病患者肾组织中肾素表达及血浆 AngⅡ、CsA早晨服药后2 h血浓度(C2)水平,并结合临床表现进行分析。(2)体外培养人脐静脉内皮细胞株(HUVEC)、大鼠系膜细胞株(MC),经不同浓度CsA(0、250、500、1000μg／L)孵育细胞后,用免疫组化和放免方法测定肾素的表达及AngⅡ的含量。结果慢性CsA肾病组肾素指数与对照组比较显著增高(P<0．01);血浆AngⅡ、C2水平高于对照组,但无显著性差异 [(122．69±26．73)pg／ml比(121．88±36．35)pg／ml,P=0．977,(719．04±55．89)pg／ml比(658．80± 90．78)pg／ml,P=0．196]。CsA在一定浓度范围内呈剂量依赖刺激HUVEC、MC分泌AngⅡ及上调肾素的表达。结论移植肾活检可避免慢性CsA肾病漏诊或误诊。慢性CsA肾病肾移植患者肾组织局部RAS活化,导致血浆AngⅡ水平与肾组织局部表达不一致。CsA刺激血管内皮细胞、肾小球系膜细胞分泌AngⅡ,上调肾素的表达。阻断RAS可能有益于延缓慢性CsA肾病的进程。

Objective To detect the levels of renin and angiotensin Ⅱ in renal tissue and plasma from kidney transplantation patients suffering from chronic CsA-related nephropathy, and to explore the effect of renin-angiotensin system （RAS） on chronic cyclosporine nephropathy. Methods （1）Thirteen patients with renal biopsy-proven CsA-related nephrotoxicity were enrolled in this study, whose renal tissues were subjected to immunohistochemical staining by rabbit polyclonal anti-human renin antibody. Cyclosporine plasma level was obtained 2 hour after morning dose （C2） and angiotensin Ⅱ （AngⅡ ） plasma level was measured after allograft biopsy was performed. The relationship between renin expression and clinicopathological manifestation was also investigated. （2） Human umbilical vascular endothelial cells （HUVEC）and mesangial cells （MC）were incubated with different concentrations of CsA （0,250,500,1000 μg/L） for 24 hours. staining was used to examine lenin expression. The secretion of Ang Ⅱ in cytoplasm and culture medium was measured by radioimmunoassay. Results The histological renin index was significantly higher in specimens of chronic CsA nephropathy than that of control （5.20±0.40 vs. 2.30±0.24,P〈0.01）. The plasma levels of C2 and AngⅡ in chronic CsA nephropathy group were higher than those in control group,but no significant difference was found [（122.69±26.73）pg/ml vs.（121.88±36.35）pg/ml,P= 0.977, （719.04±55.89）pg/ml vs. （658.80±90.78）pg/ml,P=0.196,respectively].In vitro, renin expression increased significantly both in HUVEC and MC after the cells were incubated with CsA for 24 hours （231.50±12.10 vs.182.34±11.51,P〈 0.05; 176.35±14.51 vs.153.36±11.11,P〈0.05）. CsA also stimulated the secretion of AngⅡ in HUVEC and MC in a dose-dependent manner. Conclusions Renal allograft biopsy is important to differentiate chronic CsA-related nephropathy from chronic rejection. The intrarenal R.AS may play an important role in chronic CsA-related nephropathy. The histological lesion of CsA nephrotoxicity fails to correspond spontaneously to either the change of C2 level or the change of AngⅡ plasma level. CsA stimulates the secretion of AngⅡ and the expression of renin in HUVEC and MC. Blockage of RAS may be helpful for therapeutic intervention in the progression of chronic CsA-related nephropathy.