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

总结/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肥胖的主要原因。 慢性肾病（CKD）及其进展为终末期肾病（ESRD）。肥胖症流行率 在过去的几十年里急剧增加。这种快速增长不能用 基因型，但可能是由于环境因素及其与基因的相互作用。母亲肥胖是 与后代患高血压的风险更大有关，并影响长期的能量平衡。虽然 心血管疾病（CVD）的遗传基础研究已经投入了相当大的努力， 有证据表明，心肾疾病的跨代非基因组原因。急性和CKD是 在世界范围内和美国，终末期肾病的发病率，特别是糖尿病肾病的发病率， 同时伴随着肥胖和相关代谢紊乱的增加。预计终末期肾病的发病率将上升 此外，由于人口老龄化。了解当前西方生活方式对后代的风险 对于确定预防急性和CKD的潜在干预措施至关重要， 胎儿编程影响心肾疾病发展的机制。一个潜在 调节肥胖诱导的发育编程对心肾功能影响的机制是 P2 X嘌呤受体7（P2 X7 R）的过度激活。P2 X7 R是由P2 X7基因编码的蛋白质 属于ATP嘌呤受体家族，其激活触发Ca 2+、胞浆Ca 2 + 超负荷、内质网（ER）应激和细胞毒性。此外，线粒体功能障碍还涉及 P2 X7 R介导的细胞死亡。P2 X7 R也可能在炎症和一些肾脏疾病中发挥关键作用 模型使用高脂喂养诱导的母体肥胖模型，我们发现P2 X7 R的表达与高脂喂养诱导的母体肥胖模型中P2 X7 R的表达相关。 在肥胖父母后代的肾脏中显著更高，表明其在肾损伤中的潜在作用 在跨代肥胖合并高血压（HT）中观察到。我们还发现雌激素受体水平的增加 肥胖父母的后代肾脏中的应激标记物和线粒体功能障碍。 肥胖诱导的发育程序和肾损伤之间的联系，喂养高脂肪饮食四周的小鼠 交配前、妊娠期和哺乳期将用于建立第一代和第二代模型， 肥胖因此，这一建议的中心假设是，肥胖和肥胖症的发展规划， 其相关的代谢异常导致P2 X7 R的激活和氧化应激的放大， 肾损伤，尤其是与HT合并时。这些与肥胖相关的代谢综合效应 异常和HT对肾损伤的作用是通过ER应激、线粒体功能障碍和细胞凋亡介导的。的 拟议中的研究将确定第一代和第二代肥胖父母是否更容易患上肥胖症。 代谢功能障碍和HT诱导的肾损伤及其机制，这可能会导致更好的 预防后代肾功能障碍的治疗方法。

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.