Key Laboratory of maternal-fetal medicine of Liaoning Province, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, China.
Department of human resource, Shengjing Hospital of China Medical University, China.
Life Sci. 2020 Oct 15;259:118276. doi: 10.1016/j.lfs.2020.118276. Epub 2020 Aug 13.
The mechanisms underlying the fetal origin of renal disease remains unknown. This study aimed to investigate the profiles of ion channel and transporter proteins in the fetal kidney in fetal growth restriction (FGR)rats, and to explore their association with the fetal origin of renal disease.
An FGR rat model was developed by administration of a low-protein diet. Then 367 differentially expressed proteins (DEPs) from quantitative proteome analysis were subjected to Ingenuity Pathway Analysis. 22 DEPs associated with ion channels/transporters were evaluated in the fetal kidney. Na+/H+ exchanger1(NHE1) and its downstream unfolded protein response (UPR) pathway were investigated. Furthermore, overexpression of NHE1 were achieved via plasmid transfection to evaluate the potential influence on the UPR pathway and cell apoptosis in human proximal tubular epithelial cell line HK2 cells.
Findings were as follows: 1) In the FGR fetal kidney, aquaporin 2/4, solute carrier (SLC) 8a1, 33a1, etc. were downregulated, whereas other transporters including SLC 2a1, 4a1, 9a1, 29a3, etc. were upregulated. 2) NHE1 mRNA levels were markedly elevated in the FGR fetus. Further investigation revealed an increase in the UPR pathway regulators. 3) In vitro study showed that NHE1 overexpression in HK2 cells significantly induced expression of the endoplasmic reticulum stress (ERS) regulators and led to a decrease in the anti-apoptotic potential.
We speculate that maternal protein malnutrition causes dysregulation of ion channels/transporters in the fetal kidney. Upregulated NHE1 may activate the UPR pathway and induce cell apoptosis thus leading to impairment of kidney function.
胎儿期起源的肾脏疾病的发病机制尚不清楚。本研究旨在探讨胎儿生长受限（FGR）大鼠胎儿肾脏中离子通道和转运蛋白的特征，并探讨其与胎儿期起源的肾脏疾病的关系。
采用低蛋白饮食建立 FGR 大鼠模型。然后对定量蛋白质组分析中的 367 个差异表达蛋白（DEPs）进行 Ingenuity 通路分析。评估了胎儿肾脏中与离子通道/转运体相关的 22 个 DEP。研究了钠氢交换蛋白 1（NHE1）及其下游未折叠蛋白反应（UPR）通路。此外，通过质粒转染过表达 NHE1，评估其对人近端肾小管上皮细胞系 HK2 细胞 UPR 通路和细胞凋亡的潜在影响。
1）在 FGR 胎儿肾脏中，水通道蛋白 2/4、溶质载体（SLC）8a1、33a1 等下调，而其他转运体包括 SLC 2a1、4a1、9a1、29a3 等上调。2）NHE1mRNA 在 FGR 胎儿中明显升高。进一步研究表明 UPR 通路调节剂增加。3）在体外研究中，HK2 细胞中 NHE1 的过表达显著诱导内质网应激（ERS）调节剂的表达，并导致抗凋亡能力下降。
我们推测母体蛋白质营养不良导致胎儿肾脏离子通道/转运体失调。上调的 NHE1 可能激活 UPR 通路并诱导细胞凋亡，从而导致肾功能损害。
