基于TRPC6/CaMKKβ/AMPK/mTOR信号通路探讨潜阳育阴颗粒调控肾脏自噬水平治疗高血压肾损伤的机制

Qianyang Yuyin Granule (QYG) is an in-hospital Chinese herbal preparation of the Affiliated Hospital of Nanjing University of Chinese Medicine. It is used for the treatment of hypertensive renal injury and has been shown to significantly reduce urine protein levels and relieve kidney damage. Recent studies have found that hypertensive renal injury is associated with an excessive upregulation of autophagy, mediated by overactivation of the TRPC6/CaMKKβ/AMPK/mTOR signaling pathway. Based on this, we propose that QYG ameliorates hypertensive renal injury by modulating autophagy. Specifically, we hypothesize that QYG regulates podocyte autophagy by interfering with TRPC6/Ca2+ in the Ca2+/CaMKKβ/AMPK/mTOR signaling pathway. This project intends to use RNA interference, calcium imaging, and other experimental techniques to explore whether QYG can down-regulate TRPC6 and thereby suppress CaMKKβ/AMPK/mTOR-mediated autophagy. The implementation of this proposed study can provide a scientific basis for the treatment of hypertensive kidney damage by Chinese medicine.

潜阳育阴颗粒（QYG）是南京中医药大学附属医院院内制剂，用于高血压肾损伤的治疗，可显著降低尿蛋白，缓解肾损伤。近期研究发现高血压肾损伤与自噬水平异常相关，激活TRPC6/CaMKKβ/AMPK/mTOR介导的自噬水平上调，可能促进高血压肾损伤隐匿恶性进展。基于此，我们提出假说：QYG通过调控Ca2+/CaMKKβ/AMPK/mTOR介导的自噬水平改善高血压肾损伤；并且在此过程中，QYG可能主要通过干预足细胞TRPC6/Ca2+的来调控CaMKKβ/AMPK/mTOR，调节自噬水平。本项目拟采用RNA干扰、钙成像等实验技术，在前期研究的基础上进一步探讨QYG是否通过干预TRPC6来下调CaMKKβ/AMPK/mTOR，从而抑制过度激活的自噬水平。本课题的实施可为中医药治疗高血压肾损伤提供科学依据。

高血压肾病发病率呈上升趋势，目前仅强调降压达标对肾功能保护仍有欠缺。我们既往研究表明，潜阳育阴颗粒（QYYYG）在临床上用于高血压肾损害（HRD）治疗，可显著降低尿蛋白。足细胞损伤是蛋白尿产生的重要环节。本研究中，我们发现QYYYG减轻自发性高血压大鼠（SHR）的HRD，改善SHR肾脏中异常自噬水平。体外实验显示，QYYYG对血管紧张素II（Ang II）诱导的足细胞损伤具有保护作用。此外，QYYYG下调了Ang II诱导的足细胞的自噬水平，抑制Ang II介导的TRPC6激活、Ca2+内流和CaMKKβ-AMPK通路的激活。过表达TRPC6导致足细胞CaMKKβ、AMPK的明显激活和自噬水平的上调，而QYYYG显著减弱了这些作用。综上，我们的研究阐明了QYYYG通过TRPC6-CaMKKβ-AMPK-mTOR通路调控足细胞异常自噬发挥HRD保护作用。因此，本研究为高血压肾损害的中医药防治提供了新的靶点和思路。