高胰岛素血症通过AQP1/NHE3介导的管球反馈失衡在“IGT肾病”发病中的作用及大黄素联合黄连素的干预研究

更早干预时机和靶点是糖尿病肾病防治关键所在。基于前期工作，课题组创新提出“IGT肾病”概念，代偿性高胰岛素血症参与肾脏高滤过，且可导致肾小管周微循环障碍。缺氧促进肾小管AQP1/NHE3介导的水钠重吸收，调控管球反馈。据此提出高胰岛素血症所致肾小管缺氧促进AQP1/NHE3介导的水钠重吸收，导致管球反馈失衡、肾脏高滤过，参与“IGT肾病”发病假说。IGT属中医脾瘅范畴，泻心汤有较好肾保护作用。课题以OLETF大鼠和AQP1-/-OLETF大鼠为对象，观察IGT/DM各阶段AQP1/NHE3介导的肾小管重吸收率、肾小球滤过率、管球反馈失衡等变化；以肾小管上皮细胞为对象，探讨缺氧影响肾小管细胞水钠重吸收机制，揭示高胰岛素血症介导的管球反馈失衡在IGT肾病中的作用；应用组分配伍法观察泻心汤主药组分大黄素和黄连素对IGT肾病的防治作用。结果将为糖尿病肾病早期防治提供新思路，丰富中医“治未病”理论。

The prevention of diabetic kidney disease lies in early timing and targets of intervention. Based on our previous work, we have come up with a concept of “IGT nephropathy”. Compensatory hyperinsulinemia is involved in renal hyperfiltration and may cause disturbance of peritubular microcirculation. Hypoxia promotes the reabsorption of water and sodium via AQP1/NHE3 and regulates tubuloglomerular feedback. Therefore, we hypothesized that hypoxia caused by hyperinsulinemia promotes the reabsorption of water and sodium mediated by AQP1/NHE3 in tubules, leading to imbalance of tubuloglomerular feedback and hyperfiltration of the kidney, and resulting in “IGT nephropathy”. IGT belongs to “Pi-dan”, and Xie-xin Decoction has protective effects on the kidney. In this study, we will study the renal tubular reabsorption rate, glomerular filtration rate and imbalance of tubuloglomerular feedback mediated by AQP1/ NHE3 at IGT and DM stages of OLETF rats and AQP1-/-OLETF rats. In vitro experiments, we will use renal tubular epithelial cells to explore the mechanism of water and sodium reabsorption in hypoxia condition, and to reveal the role of hyperinsulinemia in mediating the imbalance of tubuloglomerular feedback in “IGT nephropathy”. In addition, we will observe the effects of the two main components of xie-xin decoction, emodin and berberin, on prevention and treatment of “IGT nephropathy”. The results will provide new ideas for the early prevention and treatment of diabetic kidney disease, and enrich the “preventive treatment of disease” theory of Traditional Chinese Medicine.