Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China.
Department of Internal Medicine, Division of Nephrology, West China School of Medicine, Sichuan University, Chengdu 610041, China.
Chin Med J (Engl). 2017 Sep 20;130(18):2156-2162. doi: 10.4103/0366-6999.213971.
: Cyclosporine A (CsA) is a commonly used clinical immunosuppressant. However, CsA exposure in rabbits during the gestation period was shown to cause a postnatal decrease in the number of nephrons, with the effects remaining unknown. In this study, we aimed to explore the effects of CsA on metanephros development in the pregnant BALB/c mice.
: Pregnant mice were randomly divided into two groups, and CsA (10 mg·kg·d) was subcutaneously injected from gestation day 10.5 to day 16.5 in the CsA group, whereas a comparable volume of normal saline was given to the control group. All of the mice were sacrificed on gestation day 17.5 and serum CsA concentration was measured. The fetuses were removed and weighed, and their kidneys were prepared for histological assessment and polymerase chain reaction assay. In an in vitro experiment, embryo kidneys of fetal mice on gestation day 12.5 were used, and CsA (10 μmol/L) was added in the culture of the CsA group. The growth pattern of the ureteric bud and nephrons was assessed by lectin staining.
: No significant differences in the weight of embryo (4.54 ± 1.22 vs. 3.26 ± 1.09 mg) were observed between the CsA and control groups, the thickness of the cortical (510.0 ± 30.3 vs. 350.0 ± 29.7 μm, P < 0.05) and nephrogenic zone (272.5 ± 17.2 vs. 173.3 ± 24.0 μm, P < 0.05), and the number of glomeruli (36.5 ± 0.7 vs. 27.5 ± 2.1, P < 0.05) were reduced in the CsA group when compared to the control group. The cell proliferation of Ki-67 positive index between control and CsA group (307.0 ± 20.0 vs. 219.0 ± 25.0, P < 0.05) in the nephrogenic zone was decreased with the increase of apoptotic cells (17.0 ± 2.0 vs. 159.0 ± 33.0, P < 0.05). The mRNA expression of WT-1, Pax2, and Pax8 was downregulated by CsA treatment. As for the in vitro CsA group, the branch number of the ureteric bud was decreased in the CsA-treated group with the nephrons missing in contrast to control after the incubation for 24 h and 72 h (all P < 0.0001).
: Treatment of CsA suppressed metanephros development in the pregnant mice; however, the potential action of mechanism needs to be further investigated.
环孢素 A（CsA）是一种常用的临床免疫抑制剂。然而，已有研究表明 CsA 会导致妊娠兔在胚胎期暴露后，肾单位数量减少，但具体作用机制尚不清楚。本研究旨在探讨 CsA 对 BALB/c 孕鼠后肾发生的影响。
将妊娠小鼠随机分为两组，CsA 组从妊娠第 10.5 天至第 16.5 天每天皮下注射 10mg·kg·d 的 CsA，对照组给予等量生理盐水。妊娠第 17.5 天处死所有小鼠，测量血清 CsA 浓度。取出胎鼠并称重，取其肾脏进行组织学评估和聚合酶链反应检测。在体外实验中，使用妊娠第 12.5 天胎鼠的胚胎肾脏，在 CsA 组的培养中加入 10μmol/L 的 CsA。通过凝集素染色评估输尿管芽和肾单位的生长模式。
CsA 组和对照组胎鼠的体重（4.54±1.22 比 3.26±1.09 mg）、皮质厚度（510.0±30.3 比 350.0±29.7 μm，P＜0.05）和肾发生区厚度（272.5±17.2 比 173.3±24.0 μm，P＜0.05）以及肾小球数量（36.5±0.7 比 27.5±2.1，P＜0.05）均减少。与对照组相比，CsA 组肾发生区 Ki-67 阳性细胞增殖指数（307.0±20.0 比 219.0±25.0，P＜0.05）降低，凋亡细胞增多（17.0±2.0 比 159.0±33.0，P＜0.05）。WT-1、Pax2 和 Pax8 的 mRNA 表达水平均被 CsA 下调。在体外 CsA 组，孵育 24 h 和 72 h 后，CsA 处理组输尿管芽分支数量减少，与对照组相比肾单位缺失（均 P＜0.0001）。
CsA 处理抑制了孕鼠后肾发生；但其潜在作用机制仍需进一步研究。
