Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8552767 | Toxicology | 2018 | 11 Pages |
Abstract
This study aimed to prove that prenatal ethanol exposure (PEE) can induce nephrotic syndrome in male rat offspring and to explore the underlying intrauterine programming mechanisms. Pregnant Wistar rats were intragastrically administered ethanol (4â¯g/kgâ¯d) from gestational day (GD) 9 to GD 20, and the male fetuses were delivered by cesarean section at GD20 and the male adult offspring were euthanized at postnatal week (PW) 24. In vitro, the primary metanephric mesenchyme cells were treated with ethanol at concentrations of 15-60â¯mM. The results indicated that the kidneys of adult offspring in the PEE group exhibited glomerulosclerosis as well as interstitial fibrosis. The levels of serum creatinine and urine protein were elevated; the serum total cholesterol level was increased and the serum albumin concentration was reduced. In the fetal kidney, developmental retardation was presented in the PEE group via pathological examinations, accompanied by the expressional inhibition of the glial-cell-line-derived neurotrophic factor/c-ret tyrosine kinase receptor (GDNF/c-ret) signaling pathway. Although serum angiotensin II (Ang II) level and the gene expression of renal angiotensin-converting enzyme (ACE) were increased in the PEE group, the expression of renal angiotensin II type 2 receptor (AT2R) was significantly inhibited, accompanied by a reduction in the H3K27ac level on the AT2R gene promoter. In the non-classical renin-angiotensin system (RAS), the expression of renal angiotensin converting enzyme 2 (ACE2) and Mas receptor (MasR) were inhibited in the PEE group. The above changes of the classical and non-classical RAS all sustained from utero to adulthood. In vitro, ethanol elevated the gene expression of ACE and angiotensin II type 1a receptor (AT1aR) whereas it reduced the expression of AT2R, ACE2, and MasR, accompanied by a reduction in the H3K27ac level on AT2R gene promoter. Taken together, these results suggested that PEE can induce fetal kidney developmental retardation and adult nephrotic syndrome, and direct regulation of ethanol to the renal RAS was involved in the mechanism of nephrotic syndrome induced by PEE.
Keywords
PI3KPax2AT2RAT1ARangiotensin II type 1a receptorMODGDNFACE2TGF-βH3K27acH3K14acSPFH3K9acACEGAPDHRASIUGRAngiotensin 1–7Angiotensin-converting enzymeAngiotensin-converting enzyme 2Angiotensin IIAngiotensinogenPEEperiodic acid-Schifftransforming growth factor-βMasson's trichromekidney developmentc-Retpaired box 2ureteric budBUNAng IIgestational daypostnatal daynephrotic syndromerenin-angiotensin systemGlial-cell-line-derived neurotrophic factorphosphoinositide-3-kinasePrenatal ethanol exposurenephric ductintrauterine growth restrictionmean optical densityPASblood urea nitrogenAGTpostnatal weekHematoxylin and Eosinspecific pathogen freeserum creatininetotal cholesterolAngiotensin II type 2 receptorMas receptorSCR
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Authors
Yanan Zhu, Na Zuo, Bin Li, Ying Xiong, Haiyun Chen, Hangyuan He, Zhaoxia Sun, Shuangshuang Hu, Hui Cheng, Ying Ao, Hui Wang,