孕期脂多糖暴露对子代大鼠肾脏多巴胺D1受体介导的尿钠排泄的影响及机制研究

生命早期宫内不良因素刺激可改变子代成年表型，如高血压。我们发现孕期脂多糖（LPS）暴露引起子代血压升高及24小时尿钠排泄降低，但机制不清。近年研究表明肾脏多巴胺D1R受体是尿钠排泄及血压调控的重要因素。我们初步发现孕期LPS暴露子代肾脏D1R表达降低及磷酸化水平升高。因此，我们推测孕期LPS暴露子代大鼠尿钠排泄功能降低与肾脏D1R功能受损有关。另外，肾脏D1R磷酸化主要由于GRK4活性升高导致，而氧化应激是GRK4活性升高重要原因。我们前期发现，孕期LPS干预子代体内氧化与抗氧化能力失衡。因此，我们进一步假设，孕期LPS暴露可通过氧化应激引起肾脏GRK4活性升高，并导致D1R过度磷酸化及其介导的尿钠排泄功能受损，血压升高。该项目拟研究并证实高血压状态下肾脏D1R介导的尿钠排泄功能受损可能源于生命早期宫内不良因素刺激所致，并为高血压的"胚胎源性学说"提供有力证据，为高血压的防治提供新启示。

Adverse environment in early life can modulate adult phenotype, including hypertension. Our study showed maternal lipopolysaccharide (LPS) exposure results in increased blood pressure and decreased natriuresis in offspring, but the exact mechanisms are not clear. Renal dopamine D1 receptor is now recognized to serve an important role in the regulation of blood pressure and sodium balance. Our preliminary result suggested that there are decreased protein expression and increased phosphorylation of renal D1R in LPS-treated offspring.We presumed that the decreased natriuresis is linked to dysfuncton of renal D1R. In addition, the hyper-phosphorylation of D1R is mainly caused by increased GRK4 activity, which can be rugulated by oxidative stress. We also found that there is increased ROS in LPS-treated offspring. We further presumed that prenatal LPS exposure results in elevated oxidative stress, via increased GRK4 activity, impairs renal D1R function, and leads to hypertension ultimately. Our study will discuss and confirm that dysfunction of renal D1R could be programmed by adverse environment in utero, and provide strong evidence for fetal programming of hypertension, and provide a new idea on prevention and cure for hypertension.