GRK4甲基化在寒冷应激孕鼠子代高血压发生中的作用

Adverse environment in early life can modulate adult phenotype. Our study showed pregnancy cold stress can induce offering rats hypertension and the dysfunction of natriuresis, 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 of renal D1R in cold-induced offspring. It prompt that the decreased natriuresis is linked to dysfuncton of renal D1R. In addition, GRK4 is the main reason for the decline of D1 receptor in hypertension. Our previous experiments found that there are increased protein expression of renal GRK4 in cold-induced offspring. Due to the cold exposure may alter the apparent genetic, while methylation is one of the main forms of apparent genetic. Therefore, we hypothesized that prenatal cold-induced results in GRK4 methylation, via increased GRK4 activity, impairs renal D1R function, and leads to hypertension ultimately. Our study will help further improve the mechanisms of hypertension.

孕期不良刺激可以引起子代表型改变。我们发现孕期寒冷刺激可以导致子代大鼠血压升高，尿钠排泄功能障碍，但是机制不清楚。肾脏多巴胺D1R受体是尿钠排泄及血压调控的重要因素。我们初步发现孕期寒冷刺激子代肾脏D1R表达降低，提示孕期寒冷刺激子代大鼠尿钠排泄功能降低与肾脏D1R功能受损有关。另外，GRK4是高血压D1R功能下降的主要原因。我们前期实验发现寒冷子代大鼠肾脏GRK4表达升高。由于寒冷可改变基因表观遗传，而甲基化是GRK4表观遗传的主要形式之一，因此，我们推测孕期寒冷刺激可通过甲基化引起肾脏GRK4活性升高，并导致D1R表达下调及其介导的尿钠排泄功能受损，血压升高。该研究有利于进一步完善寒冷在高血压的发病机制理论，为防治高血压提供干预靶点。

目的：寒冷刺激使血压升高的重要因素之一。孕期不良刺激可以引起子代表型改变。但是孕期寒冷是否可以引起血压升高其机制并不清楚。方法：本研究建立了孕期寒冷刺激子代大鼠高血压模型，利用鼠尾无创血压检测技术检测子代大鼠的血压，24h尿钠排泄变化，利用阻滞剂等药物、去交感神经手术分析了其中枢及外周交感神经兴奋性变化，以免疫组化等技术研究了孕期寒冷刺激对子代室旁核神经元兴奋性及AT1受体和炎症因子表达和功能的影响。结果：孕期寒冷刺激使子代外周血管D1受体表达减少，血管痉挛降低了子代大鼠外周血管舒张功能，导致小动脉痉挛，增高了血压。这一作用与孕期寒冷刺激增加子代大鼠中枢神经兴奋性及外周的交感神经兴奋性有关。结果发现孕期寒冷刺激增加室旁核神经元的兴奋性及AT1受体的表达和功能，促进了中枢炎症因子IL-1/IL-6的表达。这是外周交感神经兴奋性增高的重要原因。结论：孕期寒冷刺激通过增加子代大鼠室旁核神经元兴奋水平，激活中枢的RAS系统和外周的交感神经，引起小血管痉挛和肾脏水钠潴留，增高血压。