Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Lab Invest. 2023 Feb;103(2):100015. doi: 10.1016/j.labinv.2022.100015. Epub 2023 Jan 10.
Exogenous erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). Concerns about the possible adverse effect of EPO on the progression of CKD have been raised owing to nonerythroid cell effects. We investigated the effects of low-dose EPO, independent of correcting anemia, on existing glomerulosclerosis. Adult mice underwent 5/6 nephrectomy and were randomized into the following 4 groups at week 8 after surgery: vehicle (VEH), losartan (angiotensin II type 1 receptor blocker [ARB]), darbepoetin-α (DA), or combination (DA+ARB). Four weeks later, mice were euthanized, followed by evaluation of renal structure and function. Glomerular endothelial cells and podocytes were cultured to evaluate the effects of DA on cell migration, apoptosis, and Akt signaling. ARB reduced blood pressure, albuminuria, and the level of serum creatinine and increased hematocrit compared with VEH, whereas low-dose DA only reduced the level of serum creatinine. Combination treatment showed a trend to increase hematocrit and survival compared with ARB alone. Combination treatment but not ARB alone significantly reduced the progression of glomerulosclerosis compared with VEH. Low-dose DA resulted in more preserved glomerular and peritubular capillary endothelial cells with increased p-Akt and even further endothelial cell preservation in combination with ARB. In cultured glomerular endothelial cells, angiotensin II induced more apoptosis, reduced migration, and decreased p-Flk1, a receptor for the proangiogenic vascular endothelial growth factor. DA counteracted these injuries and increased p-Akt, a key factor in angiogenesis and cell survival. DA also protected cultured podocytes against transforming growth factor β-induced apoptosis and synaptopodin loss. Low-dose EPO directly protects glomerular and peritubular endothelial cells via Akt phosphorylation. Therefore, treatment using a combination of low-dose EPO and ARB results in less progression of glomerulosclerosis in an experimental CKD model.
外源性促红细胞生成素（EPO）用于治疗慢性肾脏病（CKD）患者的贫血。由于非红细胞细胞效应，人们对 EPO 可能对 CKD 进展产生的不良影响表示担忧。我们研究了低剂量 EPO 对已存在肾小球硬化的影响，这种影响独立于纠正贫血。成年小鼠接受 5/6 肾切除术，术后第 8 周随机分为以下 4 组：载体（VEH）、氯沙坦（血管紧张素 II 型 1 型受体阻滞剂[ARB]）、达贝泊汀-α（DA）或联合（DA+ARB）。4 周后，处死小鼠，然后评估肾脏结构和功能。培养肾小球内皮细胞和足细胞，以评估 DA 对细胞迁移、凋亡和 Akt 信号的影响。ARB 降低血压、蛋白尿、血清肌酐水平和增加血细胞比容，与 VEH 相比，而低剂量 DA 仅降低血清肌酐水平。与 ARB 单独治疗相比，联合治疗显示出增加血细胞比容和存活率的趋势。与 VEH 相比，联合治疗但不是 ARB 单独治疗可显著减缓肾小球硬化的进展。与 VEH 相比，低剂量 DA 导致更多的肾小球和肾小管周围毛细血管内皮细胞保存，同时增加了 p-Akt，甚至在与 ARB 联合治疗时，内皮细胞保存更为明显。在培养的肾小球内皮细胞中，血管紧张素 II 诱导更多的细胞凋亡，降低迁移，并降低受体 Flk1，一种促血管生成血管内皮生长因子的受体。DA 对抗这些损伤并增加 p-Akt，这是血管生成和细胞存活的关键因素。DA 还保护培养的足细胞免受转化生长因子β诱导的凋亡和 synaptopodin 丢失。低剂量 EPO 通过 Akt 磷酸化直接保护肾小球和肾小管周围内皮细胞。因此，在实验性 CKD 模型中，使用低剂量 EPO 和 ARB 的联合治疗可导致肾小球硬化进展减少。
