Mensah-Brown E P K, Obineche E N, Galadari S, Chandranath E, Shahin A, Ahmed I, Patel S M, Adem A
Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
Cytokine. 2005 Aug 7;31(3):180-90. doi: 10.1016/j.cyto.2005.04.006.
The role of inflammatory cytokines in the pathogenesis of diabetic nephropathy has been studied in streptozotocin-induced diabetic rats. Rat kidneys were examined by light and electron microscopy and kidney homogenates were also analyzed by Western blot and flow cytometry for the expression of markers of inflammation namely, CD4+ and CD8+ T cells, macrophages, MHC classes I and II, the proinflammatory cytokines tumor necrosis factor-alpha, interferon-gamma and nitric oxide (NO). Light and electron microscope examination revealed infiltration of mononuclear cells throughout the renal parenchyma, with the glomeruli being more severely affected especially at 8 months after disease induction. Western blot and flow cytometric analyses revealed the infiltrating cells to be CD4+ T cells, CD8+ T cells and macrophages. Western blot analyses also revealed increased expression of the proinflammatory and Th1 cytokines tumor necrosis factor-alpha, interferon-gamma as well as nitric oxide. Using flow cytometry, we have shown that the difference in expression of CD4+ T cells in control and diabetic kidneys is more significant at 1 month than at 8 months, while expression of CD8+ T cells is more significant at 8 months. We speculate therefore that diabetic nephropathy is probably initiated and driven by a Th1 process. CD8+ T cells, however, become more significant at later stages of the disease when tissue loss is evident. Since NO induction also occurs only after 8 months, we hypothesize that NO might be significant for the later stages of the disease. Our data implicate inflammation in the pathogenesis of diabetic nephropathy in view of the overexpression of the proinflammatory cytokines TNF-alpha and IFN-gamma and the cells that secrete them in the early and late phases of the disease.
炎症细胞因子在链脲佐菌素诱导的糖尿病大鼠糖尿病肾病发病机制中的作用已得到研究。通过光镜和电镜检查大鼠肾脏，并用蛋白质免疫印迹法和流式细胞术分析肾脏匀浆中炎症标志物的表达，这些标志物包括CD4⁺和CD8⁺ T细胞、巨噬细胞、I类和II类主要组织相容性复合体、促炎细胞因子肿瘤坏死因子-α、干扰素-γ和一氧化氮（NO）。光镜和电镜检查显示整个肾实质有单核细胞浸润，肾小球受影响更严重，尤其是在疾病诱导后8个月。蛋白质免疫印迹法和流式细胞术分析显示浸润细胞为CD4⁺ T细胞、CD8⁺ T细胞和巨噬细胞。蛋白质免疫印迹法分析还显示促炎和Th1细胞因子肿瘤坏死因子-α、干扰素-γ以及一氧化氮的表达增加。通过流式细胞术，我们发现对照肾脏和糖尿病肾脏中CD4⁺ T细胞表达的差异在1个月时比8个月时更显著，而CD8⁺ T细胞的表达在8个月时更显著。因此，我们推测糖尿病肾病可能由Th1过程启动和驱动。然而，在疾病后期组织明显受损时，CD8⁺ T细胞变得更为重要。由于一氧化氮的诱导也仅在8个月后发生，我们推测一氧化氮可能在疾病后期起重要作用。鉴于促炎细胞因子TNF-α和IFN-γ及其在疾病早期和晚期分泌细胞的过度表达，我们的数据表明炎症参与了糖尿病肾病的发病机制。
