The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration
The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration
复制标题
脯氨酰羟化酶抑制剂对大鼠残肾缺氧诱导因子激活的有益和有害作用的平衡取决于给药时机
DOI：
10.1093/ndt/gfr754
复制
发表时间：
2012-08-01
影响因子：
6.1
通讯作者：
Ding, Xiaoqiang
中科院分区：
文献类型：
--
作者：
Yu, Xiaofang;Fang, Yi;Ding, Xiaoqiang
肾脏中的慢性缺氧已被认为是导致最终肾衰竭的慢性肾脏疾病（CKD）进展的最终共同途径。缺氧诱导因子（HIF）的激活可能为缺氧组织的保护提供了一种有前途的方法，但HIF激活对CKD的影响仍存在争议。在本研究中，我们在大鼠残肾（RK）模型中研究了HIF激活对CKD的有益或有害影响，在肾大部切除术后一周，大鼠被随机分组，并接受脯氨酰羟化酶（PHD）抑制剂L-含羞草碱（L-Mim）的特殊给药，如下：在早期长期L-Mim治疗组中，在第212周给予L-Mim;晚期中期L-Mim治疗组在第412周给予L-Mim，晚期L-Mim治疗组在第812周给予L-Mim。与对照组相比，肾功能不全和III型胶原沉积增加，- 平滑肌肌动蛋白表达和艾德-1阳性巨噬细胞浸润在肾小管上皮细胞的早期长期L-Mim治疗加剧，并改善了先进的中期L-Mim治疗。终末期L-Mim处理对RK大鼠没有影响。此外，早期长期L-Mim治疗在整个时间过程中显著激活HIF-1、结缔组织生长因子（CTGF）和磷酸化Smad 3，并在终末期轻微激活HIF-2、血管内皮生长因子（VEGF）和促红细胞生成素（EPO），而晚期中期L-Mim治疗显著激活HIF-2、VEGF和EPO，而对HIF-1无影响。通过PHD抑制剂L-Mim的HIF-激活在大鼠RK模型中的CKD发展中具有双重作用，这取决于施用的时机和可能的HIF-的激活同种型。
Chronic hypoxia in the kidney has been suggested as a final common pathway in the progression of chronic kidney disease (CKD) leading to eventual kidney failure. Hypoxia-inducible factor (HIF) activation might offer a promising approach to the protection of hypoxic tissues, but the effect of HIF activation on CKD is still controversial. In this study, we investigated whether HIF activation had a beneficial or deleterious effect on CKD in the rat remnant kidney (RK) model.One week after a subtotal nephrectomy, rats were randomized and each received special administration of prolyl hydroxylases (PHD) inhibitor L-mimosine (L-Mim) as follows: in the early long-time L-Mim treatment group they were administered L-Mim at Weeks 212; in the advanced medium-term L-Mim treatment group they were administered L-Mim at Weeks 412 and in the end-stage L-Mim treatment group they were administered L-Mim at Weeks 812.Compared with the control group, renal dysfunction and increased collagen III deposition, -smooth muscle actin expression and ED-1-positive macrophage infiltration in tubulointerstitium were exacerbated by early long-term L-Mim treatment and improved by advanced medium-term L-Mim treatment. End-stage L-Mim treatment had no effect on RK rats. Furthermore, early long-term L-Mim treatment activated HIF-1, connective tissue growth factor (CTGF) and phospho-Smad3 prominently throughout the time course and activated HIF-2, vascular endothelial growth factor (VEGF) and erythropoietin (EPO) slightly at the end stage, while advanced medium-term L-Mim treatment activated HIF-2, VEGF and EPO significantly and had no effect on HIF-1, CTGF and phospho-Smad3.HIF- activation by PHD inhibitor L-Mim has dual roles in the development of CKD in the rat RK model depending on the timing of the administration and possibly the activated isoform of HIF-.