Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Nephrol Dial Transplant. 2012 Aug;27(8):3110-9. doi: 10.1093/ndt/gfr754. Epub 2012 Mar 6.
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 2-12; in the advanced medium-term L-Mim treatment group they were administered L-Mim at Weeks 4-12 and in the end-stage L-Mim treatment group they were administered L-Mim at Weeks 8-12.
Compared with the control group, renal dysfunction and increased collagen III deposition, α-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-1α, connective tissue growth factor (CTGF) and phospho-Smad3 prominently throughout the time course and activated HIF-2α, vascular endothelial growth factor (VEGF) and erythropoietin (EPO) slightly at the end stage, while advanced medium-term L-Mim treatment activated HIF-2α, VEGF and EPO significantly and had no effect on HIF-1α, CTGF and phospho-Smad3.
HIF-α 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-α.
慢性肾脏缺氧被认为是导致慢性肾脏病（CKD）进展并最终导致肾衰竭的共同途径。缺氧诱导因子（HIF）的激活可能为保护缺氧组织提供一种很有前途的方法，但 HIF 激活对 CKD 的影响仍存在争议。在这项研究中，我们研究了 HIF 激活对大鼠残肾（RK）模型中 CKD 的影响。
在部分肾切除术后 1 周，将大鼠随机分组，并分别给予脯氨酰羟化酶（PHD）抑制剂 L-脯氨酸（L-Mim）的特殊治疗，具体如下：早期长期 L-Mim 治疗组在第 2-12 周给予 L-Mim；中期晚期 L-Mim 治疗组在第 4-12 周给予 L-Mim；晚期 L-Mim 治疗组在第 8-12 周给予 L-Mim。
与对照组相比，早期长期 L-Mim 治疗加重了肾功能障碍和胶原 III 沉积、α-平滑肌肌动蛋白表达以及肾小管间质中 ED-1 阳性巨噬细胞浸润，而中期晚期 L-Mim 治疗则改善了这些变化。晚期 L-Mim 治疗对 RK 大鼠无影响。此外，早期长期 L-Mim 治疗在整个时间过程中明显激活了 HIF-1α、结缔组织生长因子（CTGF）和磷酸化 Smad3，而在末期轻微激活了 HIF-2α、血管内皮生长因子（VEGF）和促红细胞生成素（EPO），而中期晚期 L-Mim 治疗则明显激活了 HIF-2α、VEGF 和 EPO，对 HIF-1α、CTGF 和磷酸化 Smad3 无影响。
PHD 抑制剂 L-Mim 通过 HIF-α的激活在大鼠 RK 模型中 CKD 的发展中具有双重作用，这取决于给药时间和可能的 HIF-α激活亚型。
