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Post-Natal Inhibition of NF-?B Activation Prevents Renal Damage Caused by Prenatal LPS Exposure.

ABSTRACT: Prenatal exposure to an inflammatory stimulus has been shown to cause renal damage in offspring. Our present study explored the role of intra-renal NF-?B activation in the development of progressive renal fibrosis in offspring that underwent prenatal exposure to an inflammatory stimulus. Time-dated pregnant rats were treated with saline (control group) or 0.79 mg/kg lipopolysaccharide (LPS) through intra-peritoneal injection on gestational day 8, 10 and 12. At the age of 7 weeks, offspring from control or LPS group were treated with either tap water (Con+Ve or LPS+Ve group) or pyrollidine dithiocarbamate (PDTC, 120 mg/L), a NF-?B inhibitor, via drinking water starting (Con+PDTC or LPS+PDTC group), respectively, till the age of 20 or 68 weeks. The gross structure of kidney was assessed by hematoxylin-eosin, periodic acid-Schiff staining and Sirius red staining. The expression levels of TNF-?, IL-6, ?-smooth muscle actin (?-SMA) and renin-angiotensin system (RAS) genes were determined by real time polymerase chain reaction and/or immunohistochemical staining. Our data showed that post-natal persistent PDTC administration efficiently repressed intra-renal NF-?B activation, TNF-? and IL-6 expression. Post-natal PDTC also prevented intra-renal glycogen deposition and collagenous fiber generation as evident by the reduced expression of collagen III and interstitial ?-SMA in offspring of prenatal LPS exposure. Furthermore, post-natal PDTC administration reversed the intra-renal renin-angiotensin system (RAS) over-activity in offspring of prenatal LPS exposure. In conclusion, prenatal inflammatory exposure results in offspring's intra-renal NF-?B activation along with inflammation which cross-talked with excessive RAS activation that caused exacerbation of renal fibrosis and dysfunction in the offspring. Thus, early life prevention of NF-?B activation may be a potential preventive strategy for chronic renal inflammation and progressive renal damage.

SUBMITTER: Guo W

PROVIDER: S-EPMC4830567 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Post-Natal Inhibition of NF-κB Activation Prevents Renal Damage Caused by Prenatal LPS Exposure.

Guo Wei W Guan Xiao X Pan Xiaodong X Sun Xiongshan X Wang Fangjie F Ji Yan Y Huang Pei P Deng Yafei Y Zhang Qi Q Han Qi Q Yi Ping P Namaka Michael M Liu Ya Y Deng Youcai Y Li Xiaohui X

PloS one 20160413 4

Prenatal exposure to an inflammatory stimulus has been shown to cause renal damage in offspring. Our present study explored the role of intra-renal NF-κB activation in the development of progressive renal fibrosis in offspring that underwent prenatal exposure to an inflammatory stimulus. Time-dated pregnant rats were treated with saline (control group) or 0.79 mg/kg lipopolysaccharide (LPS) through intra-peritoneal injection on gestational day 8, 10 and 12. At the age of 7 weeks, offspring from ...[more]

PMID: 27073902

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Project description:BackgroundDespite decades of public education about dire consequences of prenatal alcohol exposure (PAE), drinking alcohol during pregnancy remains prevalent. As high as 40% of live-born infants exposed to alcohol during gestation and diagnosed with fetal alcohol syndrome have congenital heart defects that can be life-threatening. In animal models, the methyl donor betaine, found in foods such as wheat bran, quinoa, beets, and spinach, ameliorated neurobehavioral deficits associated with PAE, but effects on heart development are unknown.MethodsPreviously, we modeled a binge drinking episode during the first trimester in avian embryos. Here, we investigated whether betaine could prevent adverse effects of alcohol on heart development. Embryos exposed to ethanol (EtOH) with and without an optimal dose of betaine (5 μM) were analyzed at late developmental stages. Cardiac morphology parameters were rapidly analyzed and quantified using optical coherence tomography. DNA methylation at early stages was detected by immunofluorescent staining for 5-methylcytosine in sections of embryos treated with EtOH or cotreated with betaine.ResultsCompared to EtOH-exposed embryos, betaine-supplemented embryos had higher late-stage survival rates and fewer gross head and body defects than seen after alcohol exposure alone. Betaine also reduced the incidence of late-stage cardiac defects such as absent vessels, abnormal atrioventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine cotreatment brought measurements of great vessel diameters, interventricular septum thickness, and AV leaflet volumes in betaine-supplemented embryos close to control values. Early-stage 5-methycytosine staining revealed that DNA methylation levels were reduced by EtOH exposure and normalized by co-administration with betaine.ConclusionsThis is the first study demonstrating efficacy of the methyl donor betaine in alleviating cardiac defects associated with PAE. These findings highlight the therapeutic potential of low-concentration betaine doses in mitigating PAE-induced birth defects and have implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation.

Dataset Information

Post-Natal Inhibition of NF-?B Activation Prevents Renal Damage Caused by Prenatal LPS Exposure.

Publications

Post-Natal Inhibition of NF-κB Activation Prevents Renal Damage Caused by Prenatal LPS Exposure.

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