Liu Min, Gu Min, Wu Yichao, Zhu Pengcheng, Zhang Wei, Yin Changjun, Zhang Wei J
Nanjing Medical University First Affiliated Hospital, Jiangsu, China.
J Surg Res. 2009 Nov;157(1):e117-27. doi: 10.1016/j.jss.2008.10.018. Epub 2008 Nov 24.
Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. Recent evidences suggest that Rho and its downstream effector ROCK may be greatly involved in the progression of renal fibrosis. Inhibition of Rho/ROCK pathway might interact with the inflammatory process in the renal interstitium, and antagonize the process of epithelial-to-mesenchymal transition (EMT). We hypothesized that Y-27632 could inhibit the chronic inflammatory process and prevent the progression of CAN.
Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. Lewis to Lewis rat kidney transplantation was served as the syngeneic control (Syn group). Allograft recipients were randomized and treated with either cyclosporine A alone (Allo group), or in combination with Y-27632 (30 mg/kg body weight/d intragastric, Y-27632 group). Renal function and urine protein excretion levels of the rats were analyzed. Animals were sacrificed 12 wk post-transplantation for histological and immunohistochemical studies, as well as analysis of the expression levels of chemokines, transforming growth factor (TGF-beta) 1 and alpha smooth muscle actin (alpha-SMA).
Renal function deteriorated progressively in the Allo group, and there was typical CAN morphology in the kidneys. However, Y-27632-treatment significantly prevented the deterioration of graft function, lessened the level of urine protein excretion, and preserved the renal structure. Attenuation of ED1 positive mononuclear cell infiltration and amelioration of tubulointerstitial fibrosis were achieved by Y-27632 intervention. This was associated with down-regulation of the expression of tubular monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and phosphorylated NF-kappaB (which was a marker for activation). Profibrotic protein (TGF-beta1) and alpha-SMA, a marker of EMT, were significantly down-regulated by Y-27632 treatment as well.
The Rho/ROCK pathway plays an important role in the progression of CAN, and specific inhibition of Rho activity by Y-27632 showed favorable effects on blocking renal interstitial inflammation and fibrosis, thus efficiently retarding the development of CAN, which might provide us with a novel strategy to improve long-term renal graft survival.
慢性移植肾肾病（CAN）是移植肾晚期失功的主要原因。近期证据表明，Rho及其下游效应分子ROCK可能在肾纤维化进展中起重要作用。抑制Rho/ROCK信号通路可能与肾间质炎症过程相互作用，并拮抗上皮-间质转化（EMT）过程。我们推测Y-27632可抑制慢性炎症过程并阻止CAN的进展。
将Fisher（F344）大鼠肾脏原位移植到Lewis大鼠受体中。Lewis大鼠之间的肾移植作为同基因对照（Syn组）。移植肾受体随机分为单独接受环孢素A治疗（Allo组）或联合Y-27632治疗（30 mg/kg体重/天，经胃内给药，Y-27632组）。分析大鼠的肾功能和尿蛋白排泄水平。移植后12周处死动物，进行组织学和免疫组织化学研究，以及趋化因子、转化生长因子（TGF-β）1和α平滑肌肌动蛋白（α-SMA）表达水平的分析。
Allo组肾功能逐渐恶化，肾脏出现典型的CAN形态。然而，Y-27632治疗显著阻止了移植肾功能的恶化，降低了尿蛋白排泄水平，并保留了肾脏结构。Y-27632干预可减轻ED1阳性单核细胞浸润并改善肾小管间质纤维化。这与肾小管单核细胞趋化蛋白-1、调节激活正常T细胞表达和分泌的因子（RANTES）以及磷酸化核因子κB（激活标志物）表达下调有关。Y-27632治疗还可显著下调促纤维化蛋白（TGF-β1）和EMT标志物α-SMA。
Rho/ROCK信号通路在CAN进展中起重要作用，Y-27632特异性抑制Rho活性对阻断肾间质炎症和纤维化显示出良好效果，从而有效延缓CAN的发展，这可能为我们提供一种改善移植肾长期存活的新策略。
