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Title: Low functional programming of renal AT{sub 2}R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure

Abstract

Our previous study has indicated that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for glomerulosclerosis. However, whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT{sub 2}R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT{sub 1a}R)/AT{sub 2}R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected bymore » q-PCR. Moreover, AT{sub 2}R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as glomerulosclerosis of adult offspring, and the low functional programming of renal AT{sub 2}R might mediate the developmental origin of adult glomerulosclerosis. - Highlights: • Prenatal caffeine exposure induces glomerulosclerosis in adult offspring. • Prenatal caffeine exposure inhibits fetal kidney development. • Prenatal caffeine exposure causes low functional programming of renal AT{sub 2}R.« less

Authors:
 [1]; ; ;  [1];  [2]; ; ;  [1];  [2];  [1];  [1]
  1. Department of Pharmacology, School of Basic Medical Science of Wuhan University, Wuhan 430071 (China)
  2. Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China)
Publication Date:
OSTI Identifier:
22465813
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 287; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADULTS; ANGIOTENSIN; CAFFEINE; CREATININE; FETUSES; FIBROSIS; GENES; HAZARDS; KIDNEYS; MICROSCOPES; PLANT GROWTH; PROGENY; PROGRAMMING; RATS; RECEPTORS; SIGNALS; TYROSINE; URINE

Citation Formats

Ao, Ying, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071, Sun, Zhaoxia, Hu, Shuangshuang, Zuo, Na, Li, Bin, Yang, Shuailong, Xia, Liping, Wu, Yong, Wang, Linlong, He, Zheng, Wang, Hui, and Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071. Low functional programming of renal AT{sub 2}R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2015.05.007.
Ao, Ying, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071, Sun, Zhaoxia, Hu, Shuangshuang, Zuo, Na, Li, Bin, Yang, Shuailong, Xia, Liping, Wu, Yong, Wang, Linlong, He, Zheng, Wang, Hui, & Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071. Low functional programming of renal AT{sub 2}R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure. United States. https://doi.org/10.1016/J.TAAP.2015.05.007
Ao, Ying, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071, Sun, Zhaoxia, Hu, Shuangshuang, Zuo, Na, Li, Bin, Yang, Shuailong, Xia, Liping, Wu, Yong, Wang, Linlong, He, Zheng, Wang, Hui, and Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071. 2015. "Low functional programming of renal AT{sub 2}R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure". United States. https://doi.org/10.1016/J.TAAP.2015.05.007.
@article{osti_22465813,
title = {Low functional programming of renal AT{sub 2}R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure},
author = {Ao, Ying and Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071 and Sun, Zhaoxia and Hu, Shuangshuang and Zuo, Na and Li, Bin and Yang, Shuailong and Xia, Liping and Wu, Yong and Wang, Linlong and He, Zheng and Wang, Hui and Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071},
abstractNote = {Our previous study has indicated that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for glomerulosclerosis. However, whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT{sub 2}R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT{sub 1a}R)/AT{sub 2}R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT{sub 2}R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as glomerulosclerosis of adult offspring, and the low functional programming of renal AT{sub 2}R might mediate the developmental origin of adult glomerulosclerosis. - Highlights: • Prenatal caffeine exposure induces glomerulosclerosis in adult offspring. • Prenatal caffeine exposure inhibits fetal kidney development. • Prenatal caffeine exposure causes low functional programming of renal AT{sub 2}R.},
doi = {10.1016/J.TAAP.2015.05.007},
url = {https://www.osti.gov/biblio/22465813}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 287,
place = {United States},
year = {Tue Sep 01 00:00:00 EDT 2015},
month = {Tue Sep 01 00:00:00 EDT 2015}
}