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，而高血压和糖尿病又是导致 慢性肾脏病(CKD)及其进展为终末期肾病(ESRD)。肥胖症的流行 在过去的几十年里急剧增加。如此快速的增长不能用 基因型，但可能是环境因素及其与基因的相互作用造成的。母体肥胖是 与后代患高血压的风险更大相关，并影响长期的能量平衡。虽然 在研究心血管疾病(CVD)的遗传基础上投入了相当大的努力，有限 关于心肾疾病的跨代非基因组原因的证据是可用的。急性和慢性肾脏病是 在全世界和美国，终末期肾病的发病率，特别是糖尿病肾病的发病率有所上升 与此同时，肥胖和相关的代谢紊乱也在增加。预计ESRD的这种上涨将会升级 进一步由于人口老龄化。了解当前西方生活方式对子孙后代的风险 对于确定预防急性和慢性KDS的潜在干预措施至关重要，并可能提供对 胎儿程序化影响心肾疾病发展的机制。一种潜力 肥胖诱导的发育规划对心肾功能影响的机制是 通过过度激活P2X嘌呤受体7(P2X7R)。P2X7R是一种由P2X7基因编码的蛋白质 它属于ATP的嘌呤受体家族，它的激活触发了细胞内钙离子的内流 超负荷、内质网应激和细胞毒性。此外，线粒体功能障碍也与此有关。 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发挥关键作用 模特们。使用高脂喂养诱导的母体肥胖模型，我们发现P2X7R的表达是 肥胖父母的后代肾脏显著增大，提示其在肾脏损伤中的潜在作用 观察跨代肥胖合并高血压(HT)。我们还发现ER水平升高 肥胖父母子代肾脏应激标志物和线粒体功能障碍 肥胖诱导的发育规划和肾脏损伤之间的联系，喂食高脂饮食四周的小鼠 在交配前，在妊娠和哺乳期间将用于创建第一代和第二代模型 肥胖。因此，这一建议的中心假设是肥胖症和 其相关的代谢异常导致P2X7R的激活和氧化应激的放大以及 肾脏损伤，特别是合并高血压时。肥胖相关代谢的这些综合影响 内质网应激、线粒体功能障碍和细胞凋亡参与了肾脏损伤的异常和高血压的发生。这个 拟议的研究将确定第一代和第二代肥胖父母是否更容易患上 代谢功能障碍和高血压引起的肾损伤及其机制，可能导致更好的 预防子孙后代肾功能障碍的治疗方法。