GRK4在父代PM2.5暴露致子代大鼠高血压及跨代遗传中的作用及机制研究

我们既往研究发现父代PM2.5暴露可致子代鼠发生跨代高血压；芯片发现PM2.5暴露组子代肾脏GRK4、AT1R表达量均增加；抑制GRK4后，子代AT1R表达量、尿钠代谢障碍及高血压均明显恢复，提示GRK4为PM2.5影响子代血压的关键因素。进一步研究发现PM2.5处理后父代精子及子代肾脏组蛋白H3K79me3水平均明显增加；而H3K79me3的关键酶“DOT1L”却仅在父代精子中上调，提示父代精子H3K79me3是PM2.5暴露影响子代血压的记忆介质。据此我们推测：PM2.5暴露通过影响精子DOT1L表达，使H3K79me3水平上调；上调的H3K79me3作为记忆信号遗传给子代并影响肾脏GRK4表达，使得钠水潴留和血压升高，导致高血压表型及跨代传递。本项目拟用数个条件敲除小鼠(精子DOT1L和肾脏GRK4)等模型研究PM2.5致子代高血压跨代的机制，丰富高血压发生学理论。

Parental PM2.5 exposure can cause hypertension and impairment in natriuresis in rat-offspring, and this phenotype of hypertension can be transgenerationally inherited. mRNA microarray analysis shows that expression of GRK4 in F1 and F2 generation of PM2.5-exposed group was increased with expression of AT1R elevated. After inhibition of GRK4 in offspring, the expression of AT1R, natriuresis impairment and elevated blood pressure were significantly restored, which suggests that GRK4-AT1R signaling pathway plays a key role in parental PM2.5 exposure.induced hypertension in offspring rats. Further study shows that the level of tri-methylation of the 79th lysine residue of histone H3 (H3K79me3) in parental sperm, F1 and F2 kidneys are significantly higher, but the level of the key enzyme of H3K79me3 modification, telomere like silencing interfering factor 1 (DOT1L) and oxidative stress in offsprings have no significant difference compared to control.groups. However, DOT1L expression and oxidative stress in sperm of PM2.5 exposure F0 generation are found significantly higher than control group, which suggests that elevated H3K79me3 in F0 sperm induced by PM2.5 exposure can be memorized and inherited. Thus, we speculate that parental PM2.5 exposure causes oxidative stress elevation and increased DOT1L translation, which leads elevated H3K79me3 expression in F0 sperm. The inheritable H3K79me3 elevation can be stably transmitted to offsprings, mediating GRK4 highly-expression, which continuously activates GRK4-AT1R signaling pathway, further leads to impairment in natriuresis, hypertension and transgenerational inheritance of hypertension phenotype. This study provides a new understanding of the mechanism of parental PM2.5 exposure induced hypertension in offspring and its transgenerational inheritance.