Long-term consequences of parental obesity on developmental programming of cardiorenal diseases in offspring

父母肥胖对后代心肾疾病发育规划的长期影响

• 批准号: 10020982
• 负责人: Jussara M. do Carmo
• 金额: $ 27.25万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020982
• 关键词: Acute; Adult; Adverse effects; Age; Aging; Albuminuria; Apoptosis; Attenuated; Blood Pressure; Body Weight; CASP3 gene; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Death; Cells; Childhood; Chronic; Chronic Kidney Failure; Clinical; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease model; End stage renal failure; Environment; Environmental Risk Factor; Family; Fatty acid glycerol esters; Future Generations; Generations; Genes; Genetic; Genotype; High Fat Diet; Hyperglycemia; Hyperlipidemia; Hypertension; Incidence; Inflammation; Injury; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Lactation; Lead; Life Style; Link; Macula densa; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mitochondria; Modeling; Molecular; Mus; Obesity; Obesity Epidemic; Oxidative Stress; Parents; Partner in relationship; Physiological; Play; Population; Predisposition; Pregnancy; Prevalence; Proteins; Purinoceptor; Reactive Oxygen Species; Renal function; Research; Risk; Risk Factors; Role; Testing; Therapeutic; Tubular formation; United States; base; cytochrome c; cytotoxicity; endoplasmic reticulum stress; energy balance; experimental study; feeding; fetal; fetal programming; gestational weight gain; in vivo Model; inhibitor/antagonist; innovation; insight; kidney dysfunction; maternal obesity; mesangial cell; mitochondrial dysfunction; non-genomic; novel; obese mothers; offspring; prevent; protective effect; purinoceptor P2Z; receptor

SUMMARY/ABSTRACT Obesity is a major independent risk factor for hypertension and diabetes which, in turn, are leading causes of chronic kidney disease (CKD) and its progression to end stage renal disease (ESRD). The prevalence of obesity increased dramatically during the last few decades. Such rapid increase cannot be explained by changes in genotype, but may result from environmental factors and their interactions with genes. Maternal obesity is associated with a greater risk of hypertension in offspring and influences long-term energy balance. Although considerable effort has been devoted to investigating genetic bases of cardiovascular diseases (CVD), limited evidence is available on transgenerational non-genomic causes of cardiorenal diseases. Acute and CKD are growing worldwide and in the United States the incidence of ESRD, in particular diabetic nephropathy, has risen in parallel with increasing obesity and associated metabolic disorders. This rise in ESRD is projected to escalate further due to aging of the population. Understanding the risks of current Western lifestyle on future generations is crucial to determine potential interventions to prevent acute and CKDs and may provide insights into the mechanisms by which fetal programming influences the development of cardiorenal diseases. One potential mechanism mediating the effects of obesity-induced developmental programming on cardiorenal function is through excessive activation of the P2X purinoceptor 7 (P2X7R). P2X7R is a protein encoded by the P2X7 gene that belongs to the family of purinoceptors for ATP and its activation triggers an influx of Ca2+, cytosolic Ca2+ overload, endoplasmic reticulum (ER) stress and cytotoxicity. In addition, mitochondrial dysfunction is involved in P2X7R-mediated cell death. P2X7R may also play a key role in inflammation and several renal disease models. Using a model of maternal obesity induced via high fat feeding, we found that P2X7R expression is significantly greater in kidneys of offspring from obese parents, suggesting its potential role in the kidney injury observed in transgenerational obesity combined with hypertension (HT). We also found enhanced levels of ER stress markers and mitochondrial dysfunction in kidneys of offspring from obese parents.To determine a potential link between obesity-induced developmental programming and kidney injury, mice fed a high fat diet four weeks prior to mating, during gestation and lactation will be used to create first and second generation models of obesity. Therefore, the central hypothesis of this proposal is that developmental programming of obesity and its associated metabolic abnormalities lead to activation of P2X7R and amplification of oxidative stress and kidney injury, especially when combined with HT. These combined effects of obesity related metabolic abnormalities and HT on kidney injury are mediated by ER stress, mitochondrial dysfunction, and apoptosis. The proposed studies will determine whether first and second generation of obese parents are more susceptible to metabolic dysfunction and HT-induced kidney injury and the mechanisms responsible, which may lead to better therapeutic approaches to prevent kidney dysfunction in future generations.

摘要/摘要 肥胖是高血压和糖尿病的主要独立危险因素 慢性肾脏疾病（CKD）及其发展为末期肾病（ESRD）。肥胖症的流行 在过去的几十年中，急剧增加。这种快速增加无法通过变化来解释 基因型，但可能是由于环境因素及其与基因的相互作用所致。孕产妇肥胖是 与后代高血压的更大风险相关，并影响长期能量平衡。虽然 已经大量努力研究了心血管疾病的遗传基础（CVD），有限 有关于心脏疾病的跨代非基因组原因的证据。急性和CKD是 在全球范围内，在美国，ESRD的发病率，特别是糖尿病性肾病的发病率上升 与肥胖和相关代谢疾病的增加并行。 ESRD的这种兴起预计将升级 由于人口的衰老而进一步。了解当前西方生活方式对子孙后代的风险 对于确定防止急性和CKD的潜在干预措施至关重要，并可能对 胎儿编程影响心脏疾病发展的机制。一个潜力 介导肥胖引起的发育程序对心脏功能的影响的机制是 通过过度激活P2X Purinoceptor 7（P2X7R）。 P2X7R是由P2X7基因编码的蛋白质 属于ATP的Purinoceptor家族及其激活触发Ca2+​​的涌入，胞质Ca2+ 过载，内质网（ER）应力和细胞毒性。此外，涉及线粒体功能障碍 在P2X7R介导的细胞死亡中。 P2X7R也可能在炎症和几种肾脏疾病中起关键作用 型号。使用通过高脂喂养引起的母体肥胖模型，我们发现P2X7R表达是 肥胖父母的后代肾脏明显更大，这表明其在肾脏损伤中的潜在作用 在转世肥胖中观察到与高血压（HT）结合使用。我们还发现ER的水平增强 肥胖父母后代肾脏中的应力标记和线粒体功能障碍。确定潜力 肥胖引起的发育节目与肾脏损伤之间的联系，小鼠喂养高脂饮食四个星期 在交配之前，妊娠和泌乳期间将用于创建第一代和第二代模型 肥胖。因此，该提议的核心假设是肥胖和 它相关的代谢异常导致P2X7R的激活以及氧化应激的扩增和 肾脏受伤，尤其是与HT结合时。这些与肥胖相关的代谢的综合作用 肾脏损伤的异常和HT是由ER应激，线粒体功能障碍和凋亡介导的。这 拟议的研究将确定第一代和第二代肥胖父母是否更容易受到影响 代谢功能障碍和HT引起的肾脏损伤以及负责的机制，这可能会导致更好 预防子孙后代肾功能障碍的治疗方法。