The expressional disorder of the renal RAS mediates nephrotic syndrome of male rat offspring induced by prenatal ethanol exposure. (1st May 2018)

• Record Type: Journal Article
• Authors: Zhu, Yanan; Zuo, Na; Li, Bin; Xiong, Ying; Chen, Haiyun; He, Hangyuan; Sun, Zhaoxia; Hu, Shuangshuang; Cheng, Hui; Ao, Ying; Wang, Hui
• Is Part Of: Toxicology. Volume 400/401(2018)
• Page Start: 9
• Page End: 19
• Publication Date: 2018-05-01
• Subjects: PEE prenatal ethanol exposure -- GD gestational day -- PW postnatal week -- PD postnatal day -- GDNF glial-cell-line-derived neurotrophic factor -- c-ret c-ret tyrosine kinase receptor -- Ang II angiotensin II -- ACE angiotensin-converting enzyme -- AT2R angiotensin II type 2 receptor -- AT1aR angiotensin II type 1a receptor -- RAS renin-angiotensin system -- ACE2 angiotensin-converting enzyme 2 -- MasR Mas receptor -- IUGR intrauterine growth restriction -- Scr Serum creatinine -- BUN Blood urea nitrogen -- TC total cholesterol -- SPF Specific pathogen free -- HE hematoxylin and eosin -- PAS periodic acid-Schiff -- Masson Masson's trichrome -- MOD mean optical density -- Cdh11 Cadherin11 -- PI3K phosphoinositide-3-kinase -- Pax2 paired Box 2 -- GAPDH glyceraldehyde 3- phosphate dehydrogenase -- H3K9ac histone 3 Lysine 9 acetylation -- H3K14ac histone 3 Lysine 14 acetylation -- H3K27ac histone 3 Lysine 27 acetylation -- Agt angiotensinogen -- TGF-β transforming growth factor-β -- Ang(1–7) angiotensin 1–7 -- ND nephric duct -- UB ureteric bud; Prenatal ethanol exposure -- Nephrotic syndrome -- Kidney development -- Classical RAS -- Non-classical RAS; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2018.03.004
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: PEE induces fetal kidney developmental retardation and adult nephrotic syndrome. PEE causes the disorder of the renal classic and non-classical RAS. PEE inhibits the gene expression of renal AT2R in male offspring via epigenetic mechanism. Ethanol directly contributes to the dysregulation of the renal RAS. Ethanol directly inhibits the expression of H3K27ac in the AT2 R promoter in the primary metanephric mesenchyme cells. 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 (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 (AT2 R) was significantly inhibited, accompanied by a reduction in the H3K27ac level on the AT2 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 (AT1a R) whereas it reduced the expression of AT2 R, ACE2, and MasR, accompanied by a reduction in the H3K27ac level on AT2 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.