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Effects of Prenatal Exposure to Lipopolysaccharide on Adipose Development and Its Local RAS in Offspring Rats

Author: ZhangXingXing
Tutor: LiXiaoHui
School: Third Military Medical University
Course: Pharmacology
Keywords: Prenatal stress adipose tissue RAS hypertension
CLC: R544.11
Type: Master's thesis
Year: 2013
Downloads: 24
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Hypertension (Essential hypertension, EH) is characterized by arterial blood pressure,which is the most important risk factors for cardiovascular and cerebrovascular disease.Thecurrent prevalence rate is up to20%in China, it has been affected people’s quality of lifeand become one of the "killer" to threat human healthy. In the case of world-wide take aprecautionary and secondary prevention measures. The incidence rate is not falling butrising.these indications, there are some we failed to recognize that important pathogenicfactors.Our previous study found that during pregnancy inflammation (LPS) can lead to the ratoffspring hypertension and high weight. Given the nuclear transcription factor kappa-B(Nuclear factor kappa-B, NF-κB) inhibitor PDTC can be reversed the incidence ofhypertension of in rat offspring.We also observed that inflammation during pregnancy tothe offspring of hypertensive rats circulating renin-angiotensin system (renin-angiotensinsystem, RAS) did not produce a significant change. Kidney angiotensin II was significantlyincreased prompted changes in local tissue RAS may be an important mechanism of ratoffspring hypertension. RAS through the regulation of cardiovascular and renal to maintainthe balance of body water, electrolyte and blood pressure, and it’s the important body’sblood pressure regulation system. RAS is widely distributed in adipose tissue, synthesis ofvarious components of the RAS, it’s considered to be the most important source in additionto outside the liver RAS component; Adipose tissue in adult males body weight about20%to30%, females are more often. Inflammation during pregnancy in rat offspringhypertension associated with weight gain, but development of rat offspring fat and fat tissueRAS inflammation during pregnancy if there is a change and variation, and the hypertension ofoffspring rats hypertension, the development of the relationship between basic scientificquestions are to be explored.To this end, the subject to be adopted by the determination of offspring in each group. Determined their weight, wet weight of fat, the coefficient of fat and adipose tissuemorphology and fat cell differentiation. Observed rat offspring’s fat local RAS majoringredients gene and their protein levels. And gived the NF-kappa B inhibitor PDTC at thesame time, in order to observe the downturn.Our goal is to give the systematic research ofinflammation during pregnancy on offspring rat’adipose development,the RAS system andhypertension in the relationship of development.Giving the new perspective to reveal themolecular mechanisms of the pathogenesis of hypertension, and providing the newexperimental evidence for the prevention, control and treatment of high blood pressure.Methods1. The pregnant rats were randomly assigned i.e. control, LPS and LPS plus PDTCgroup. Rats in these groups were administered intraperitoneally with vehicle,0.79mg/kgLPS,100mg/kg PDTC, LPS plus PDTCwith the same dosage, respectively. LPS was givenon8th,10th and12th day while PDTC from8th to14th day during gestation. The rats inLPS group were given a vehicle injection on days9,11,13,14and rats in control group weregiven every day during8~14day.2. The measurement of systolic blood pressure in offspring ratsThe systolic blood pressure in offspring rats was measured once every four weeks at8:00~12:00a.m. every day using the standard tail-cuff method.3. The body weight of the offspring rats from birth were monitored.two weeks a time,up to16weeks. offspring rats at6th,16week of age abdominal cavity was opened, weighedwet weight, determinated the fat coefficient.4. Perirenal adipose tissue was taken when offspring rats at6th,16th week of age, fixedwith formalin, and paraffin-embedded sections were prepared,stained by HE. Adipocyte sizewas measured in randomly ten microscopic fields at40×magnification (μm).5. Real-time PCR was used to detect gene expression levels of Adipocytedifferentiation markers aP2,PPARγ,CEBP/α and CEBP/β from the6th and16th week oldoffspring rats.6. AGT, ACE, AT1, AT2gene expression levels were measured from the adipose tissueof the6th and16th week old offspring rats by Real-time PCR.7. Angiotensin II of adipose tissue was determined in offspring rats at6th and16th week of age by immunohistochemical staining (IHC). ACE, AT1and AT2protein expression level of adipose tissue in offspring rats at6th and16th week was assessedby Western blotting.Results1. As compared with control group, prenatal exposure to LPS significantly increasesthe systemic blood pressure in offspring rats at8th week age(p<0.05),12th week age(p<0.01) and16th week age(p<0.01), while prenatal exposure to LPS plus PDTC cansignificantly decrease the systolic blood pressure in offspring rats compared with LPSgroup(p<0.05).2. Prenatal exposure to lipopolysaccharide influence the adipose tissue of offspring rats2.1Prenatal exposure to lipopolysaccharide alter the body weight and the weight ofadipose tissue of offspring ratsAccording to result of0d, the body weight of LPS group increased more significantlynormal control group (p<0.05), PDTC intervention group was significantly lower (p<0.05);After birth until16th week age, LPS group’s body weight and coefficient increased moresignificantly than the normal control group (p<0.01), PDTC intervention significantly morelower than LPS group (p<0.01). These results indicated that LPS stimulation duringpregnancy can cause offspring rats weight and fat coefficient increases, while PDTC canpartly reverse it.2.2Prenatal exposure to LPS affect the growth and differentiation of AdipocyteThe6w offspring rats LPS group adipocyte size significantly reduced (vs.NS; p<0.01),adipocyte size of PDTC intervention group significantly increased (vs.LPS; p<0.05);the16w offspring rats LPS group adipocyte size significantly increased (vs.NS; p<0.01), theadipocyte size of PDTC intervention group significantly reduced (vs.LPS; p<0.05). In6woffspring rats adipocytes, aP2, CEBP/α mRNA expression was increased; the expression ofPPARγ, CEBP/β was significantly higher than NS group(p<0.01); these transcription factorexpression levels decreased in LPS plus PDTC group, PPARγ, CEBP/α, CEBP/β expressionwas significantly lower than the LPS group. At16weeks of age, the expression level ofthese transcription factors in LPS group was significantly lower than NS group(p<0.05),PDTC intervention group PPARγ,CEBP/α,CEBP/β mRNA expression was significantlyincreased(p <0.05).3. Effect of Prenatal exposure to LPS on adipose tissue RAS in offspring rats 3.1adipose tissue RAS mRNA expression in offspring ratsAt6th week, prenatal exposure to LPS significantly elevates AGT mRNA level ascompared with control group(p<0.01), the mRNA level of ACE,AT1and AT2in LPS groupis higher than control group but didn’t reach statistical significance. Compared with LPSgroup, prenatal exposure to LPS plus PDTC dropped the mRNA level of AGT, ACE, AT1,AT2, but didn’t have statistical significance. While at age of16weeks, prenatal exposure toLPS significantly elevates most components of RAS of mRNA level (p<0.01), but LPS plusPDTC group decreased these expression (p<0.05).we haven’t detected AT2mRNA level.3.2adipose tissue RAS protein expression in offspring ratsAt6th week, prenatal exposure to LPS significantly increased ANGⅡlevel ascompared with control group(p<0.05), the protein level of ACE, AT1and AT2in LPS groupis higher than control group but didn’t reach statistical significance. Compared with LPSgroup, prenatal exposure to LPS plus PDTC dropped the protein level of AngⅡ, ACE, AT1,AT2, but didn’t have statistical significance. While at age of16weeks, prenatal exposure toLPS significantly elevates all components of RAS of protein expression (p<0.05), and LPSplus PDTC group decreased these expression (p<0.05).Conclusion1. pregnancy inflammatory stimulation can cause the increase of weight and fat’scoefficient, high blood pressure in rat offspring.2. In the offspring rat childhood, pregnancy inflammatory stimulation resulted inpromoting the differentiation of adipocytes, reducing the diameter and area ofadipocytes, increasing the number of cells. Offspring rat Adult is manifested as theinhibition of adipocyte differentiation, performance of the larger diameter and area ofthe adipocytes; adipose RAS of each component changes, it is expressed as active.3. In offspring rat of pregnancy inflammatory stimulation, NF-κB inhibitor PDTC canreverse body weight, wet weight of fat, fat coefficient, the change of cell morphologyand differentiation, and can suppress the activation of the RAS and elevated bloodpressure. Prompted pregnancy inflammatory stimulation result in abnormaldevelopment of fat and activted the local RAS in offspring rat may be another importantmechanism for the pathogenesis of hypertension.

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CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Abnormal blood pressure > Hypertension > Malignant hypertension
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