13-cis retinoic acid inhibits development and progression of chronic allograft nephropathy
13-cis retinoic acid inhibits development and progression of chronic allograft nephropathy
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DOI：
10.1016/s0002-9440(10)62973-2
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发表时间：
2005-07-01
影响因子：
6
通讯作者：
Gröne, HJ
中科院分区：
文献类型：
--
作者：
Adams, J;Kiss, E;Gröne, HJ
慢性同种异体移植肾病的特征是慢性炎症和纤维化。由于类视黄醇具有抗增殖、抗炎和抗纤维化功能，因此在慢性 Fisher344 -> Lcwis 移植模型中研究了低剂量和高剂量 13-顺式视黄酸 (13cRA) 的作用。在 13cRA 动物中，无论 13cRA 给药的剂量（2 或 20 mg/kg 体重/天）和开始时间（移植后 0 或 14 天），血清肌酐均显着降低，慢性排斥损伤显着减少，包括肾小球前血管的内皮下纤维化和慢性肾小管间质损伤。浸润单核细胞的数量及其增殖活性显着减少。趋化因子的mRNA表达；在处理的同种异体移植物中，（MCP-1/CCL2、MIEP-1 α/CCL3、EP-10/CXCL10、RANTES/CCL5）和与纤维化相关的蛋白质（纤溶酶原激活剂抑制剂-1、转化生长因子-β 1以及胶原蛋白 I 和 III）显着降低。在体外，13cRA治疗大鼠的腹腔巨噬细胞活化后，炎症细胞因子的蛋白质分泌明显减少； （例如，肿瘤坏死因子-α、白细胞介素-6）。成纤维细胞中促炎趋化因子 RANTES/CCL5 X 13cRA 的抑制可以映射到包含 IRF-1 和核因子-κ B 结合元件的启动子模块，但可以排除类维生素A受体与启动子元件的直接结合。总之，l3cRA 作为一种有效的免疫抑制和抗纤维化药物，能够预防和抑制慢性同种异体移植肾病的进展。
Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflanimatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344 -> Lcwis transplantation model. in 13cRA, animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating monomiclear cells and their proliferative activity were significantly diminished. The MRNA expression of chemokines; (MCP-1/CCL2, MIEP-1 alpha/CCL3, EP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-beta 1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRAtreated rats showed a pronounced decrease in protein secretion of inflammatory cytokines; (eg, tumor necrosis factor-alpha, interieukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 X 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-kappa B binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. in summary, l3cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy.