PMID- 29548890 OWN - NLM STAT- MEDLINE DCOM- 20190115 LR - 20220410 IS - 1879-3185 (Electronic) IS - 0300-483X (Linking) VI - 400-401 DP - 2018 May 1 TI - The expressional disorder of the renal RAS mediates nephrotic syndrome of male rat offspring induced by prenatal ethanol exposure. PG - 9-19 LID - S0300-483X(18)30036-2 [pii] LID - 10.1016/j.tox.2018.03.004 [doi] AB - 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 (4 g/kg 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 15-60 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 (AT(2)R) was significantly inhibited, accompanied by a reduction in the H3K27ac level on the AT(2)R 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 (AT(1a)R) whereas it reduced the expression of AT(2)R, ACE2, and MasR, accompanied by a reduction in the H3K27ac level on AT(2)R 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. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Zhu, Yanan AU - Zhu Y AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China. FAU - Zuo, Na AU - Zuo N AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China. FAU - Li, Bin AU - Li B AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China. FAU - Xiong, Ying AU - Xiong Y AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China. FAU - Chen, Haiyun AU - Chen H AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China. FAU - He, Hangyuan AU - He H AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China. FAU - Sun, Zhaoxia AU - Sun Z AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China. FAU - Hu, Shuangshuang AU - Hu S AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China. FAU - Cheng, Hui AU - Cheng H AD - Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. FAU - Ao, Ying AU - Ao Y AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan, 430071, China. Electronic address: yingao@whu.edu.cn. FAU - Wang, Hui AU - Wang H AD - Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan, 430071, China. Electronic address: wanghui19@whu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180313 PL - Ireland TA - Toxicology JT - Toxicology JID - 0361055 RN - 3K9958V90M (Ethanol) SB - IM MH - Animals MH - Cells, Cultured MH - Ethanol/*toxicity MH - Female MH - *Gene Expression Regulation, Developmental/drug effects MH - Kidney/drug effects/metabolism/pathology MH - Male MH - Nephrotic Syndrome/*chemically induced/*metabolism/pathology MH - Pregnancy MH - Prenatal Exposure Delayed Effects/*chemically induced/*metabolism/pathology MH - Rats MH - Rats, Wistar MH - Renin-Angiotensin System/*physiology OTO - NOTNLM OT - Classical RAS OT - Kidney development OT - Nephrotic syndrome OT - Non-classical RAS OT - Prenatal ethanol exposure EDAT- 2018/03/20 06:00 MHDA- 2019/01/16 06:00 CRDT- 2018/03/18 06:00 PHST- 2018/01/04 00:00 [received] PHST- 2018/03/03 00:00 [revised] PHST- 2018/03/12 00:00 [accepted] PHST- 2018/03/20 06:00 [pubmed] PHST- 2019/01/16 06:00 [medline] PHST- 2018/03/18 06:00 [entrez] AID - S0300-483X(18)30036-2 [pii] AID - 10.1016/j.tox.2018.03.004 [doi] PST - ppublish SO - Toxicology. 2018 May 1;400-401:9-19. doi: 10.1016/j.tox.2018.03.004. Epub 2018 Mar 13.