Li Bin, Zhu Yanan, Chen Haiyun, Gao Hui, He Hangyuan, Zuo Na, Pei Linguo, Xie Wen, Chen Liaobin, Ao Ying, Wang Hui
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, 430071, China; Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, 430071, China.
Toxicology. 2019 Jan 1;411:32-42. doi: 10.1016/j.tox.2018.10.013. Epub 2018 Oct 22.
This study aimed to demonstrate that prenatal dexamethasone exposure (PDE) can induce kidney dysplasia in utero and adult glomerulosclerosis in male offspring, and to explore the underlying intrauterine programming mechanisms. Pregnant rats were subcutaneously administered dexamethasone 0.2 mg/kg.d from gestational day (GD) 9 to GD20. The male fetus on GD20 and the adult offspring at age of postnatal week 28 were analyzed. The adult offspring kidneys in the PDE group displayed glomerulosclerosis, elevated levels of serum creatinine and urine protein, ultrastructural damage of podocytes, the reduced expression levels of podocyte marker genes, nephrin and podocin. The histone 3 lysine 9 acetylation (H3K9ac) level in the promoter of renal angiotensin II receptor type 2 (AT2R) and its expression were reduced, whereas the angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PDE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio, reduced the expression level of glial-cell-line derived neurotrophic factor/c-Ret tyrosine kinase receptor (GDNF/c-Ret) signal pathway and podocyte marker genes. Moreover, the H3K9ac and H3K27ac levels of AT2R as well as the gene and protein expression levels of AT2R in fetal kidneys were inhibited by PDE. In vitro, primary metanephric mesenchyme stem cells (MMSCs) were treated with dexamethasone. Overexpression of AT2R reversed the inhibited expression of GDNF/c-Ret and podocin/nephrin induced by dexamethasone, and glucocorticoids receptor antagonist abolished the decreased H3K9ac level and gene expression of AT2R. In conclusion, PDE induced the offspring's kidney dysplasia as well as adult glomerulosclerosis, which was mediated by a sustained decrease in renal AT2R expression via decreasing the H3 K9ac level.
本研究旨在证明产前暴露于地塞米松（PDE）可导致子宫内肾发育异常以及雄性后代成年期肾小球硬化，并探索潜在的子宫内编程机制。从妊娠第9天（GD）至第20天，对怀孕大鼠皮下注射0.2mg/kg.d的地塞米松。分析了GD20时的雄性胎儿以及出生后第28周的成年后代。PDE组成年后代的肾脏表现出肾小球硬化、血清肌酐和尿蛋白水平升高、足细胞超微结构损伤、足细胞标记基因nephrin和podocin的表达水平降低。肾血管紧张素II 2型受体（AT2R）启动子中的组蛋白3赖氨酸9乙酰化（H3K9ac）水平及其表达降低，而血管紧张素II 1a型受体（AT1aR）/AT2R表达比值增加。PDE组胎儿肾脏表现出鲍曼囊腔扩大和肾小球簇缩小、皮质宽度减小以及肾发生区/皮质区比值增加、胶质细胞源性神经营养因子/c-Ret酪氨酸激酶受体（GDNF/c-Ret）信号通路和足细胞标记基因的表达水平降低。此外，PDE抑制了胎儿肾脏中AT2R的H3K9ac和H3K27ac水平以及AT2R的基因和蛋白表达水平。在体外，用地塞米松处理原代后肾间充质干细胞（MMSCs）。AT2R的过表达逆转了地塞米松诱导的GDNF/c-Ret以及podocin/nephrin表达的抑制，并且糖皮质激素受体拮抗剂消除了AT2R的H3K9ac水平降低和基因表达。总之，PDE诱导后代肾发育异常以及成年期肾小球硬化，这是通过降低H3K9ac水平导致肾脏AT2R表达持续下降介导的。
