Hamar P, Peti-Peterdi J, Szabó A, Becker G, Flach R, Rosivall L, Heemann U
Department of Nephrology, University Hospital, Essen, Germany.
Exp Nephrol. 2001 Mar-Apr;9(2):133-41. doi: 10.1159/000052604.
Glomerulosclerosis is a common feature of many end-stage renal diseases. The contribution of cellular immune mechanisms has been implicated in the development of glomerulosclerosis. We investigated whether the inhibition of lymphocyte activation influences this process in an established rat model of renal hyperfiltration.
After removal of two-thirds of their respective kidney mass, rats were treated with either tacrolimus (0.08 mg/kg/day) or vehicle until the end of the study (n = 10/group). The rats were pair-fed and proteinuria was assessed regularly. Twenty weeks after nephrectomy, creatinine clearance and systemic blood pressure were determined, and kidneys were harvested for morphological, immunohistological and PCR analysis.
In control animals, renal function started to decline from week 12, as indicated by an elevated proteinuria. Interleukin (IL)-2 and IL-2 receptor synthesis was upregulated in control animals and inhibited by tacrolimus treatment. Transforming growth factor-beta (TGF-beta(1)), platelet-derived growth factor-AA (PDGF-AA) and macrophage chemoattractant protein-1 (MCP-1) mRNA levels were upregulated in control animals, but were significantly lower in immunosuppressed hosts. Additionally, tacrolimus treatment resulted in a significant reduction of proteinuria. Morphological analysis supported these functional results; glomerular sclerosis, tubular atrophy and intimal proliferation were more pronounced in controls than in the tacrolimus group. These morphological parameters were accompanied by reduced infiltration of CD5+ (rat T-cell marker) T cells, ED1+ (rat macrophage marker) macrophages, and less intense staining for laminin and fibronectin.
A continuous treatment with tacrolimus - an inhibitor of lymphocyte proliferation - reduced the pace of glomerulosclerosis in the remnant kidney.
肾小球硬化是许多终末期肾病的常见特征。细胞免疫机制在肾小球硬化的发展中起作用。我们在已建立的肾超滤大鼠模型中研究了淋巴细胞活化的抑制是否会影响这一过程。
切除各自肾脏质量的三分之二后，大鼠接受他克莫司（0.08mg/kg/天）或赋形剂治疗直至研究结束（每组n = 10）。大鼠采用配对喂养，并定期评估蛋白尿。肾切除术后20周，测定肌酐清除率和全身血压，并采集肾脏进行形态学、免疫组织学和PCR分析。
在对照动物中，从第12周开始肾功能开始下降，表现为蛋白尿升高。对照动物中白细胞介素（IL）-2和IL-2受体合成上调，并被他克莫司治疗抑制。对照动物中转化生长因子-β（TGF-β(1)）、血小板衍生生长因子-AA（PDGF-AA）和巨噬细胞趋化蛋白-1（MCP-1）mRNA水平上调，但在免疫抑制宿主中显著降低。此外，他克莫司治疗导致蛋白尿显著减少。形态学分析支持了这些功能结果；对照动物的肾小球硬化、肾小管萎缩和内膜增生比他克莫司组更明显。这些形态学参数伴随着CD5+（大鼠T细胞标志物）T细胞、ED1+（大鼠巨噬细胞标志物）巨噬细胞浸润减少，以及层粘连蛋白和纤连蛋白染色减弱。
用他克莫司（一种淋巴细胞增殖抑制剂）持续治疗可减缓残余肾中肾小球硬化的进程。
