LRRK2调控肾小管上皮细胞自噬参与急性肾损伤的作用和机制

急性肾损伤(AKI)是临床常见的危重症。我们既往研究证实:肾小管上皮细胞自噬在AKI发生中起关键作用，但AKI时肾小管上皮细胞自噬的发生机制至今尚不清楚。最新研究发现亮氨酸重复激酶2(LRRK2)是细胞自噬的重要调控蛋白，但其在AKI发生中的作用不明。我们前期研究发现:缺血性AKI时，肾小管上皮细胞LRRK2表达增加，下调LRRK2表达致使肾小管上皮细胞自噬功能障碍、并加重AKI。由此我们提出假设:LRRK2是AKI时肾小管上皮细胞自噬的关键调控蛋白。本项目利用肾近端小管LRRK2基因条件性敲除小鼠模型、自噬报告小鼠模型和特异性LRRK2蛋白激酶抑制剂等，研究LRRK2在缺血性AKI发生中的作用、探讨LRRK2对缺血性AKI时肾小管上皮细胞自噬的调控作用和机制、阐明缺血性AKI时LRRK2表达的调控机制。本研究旨在揭示AKI时细胞自噬发生的新机制，也为开发AKI治疗的靶向药物奠定基础。

Acute kidney injury (AKI) is a major renal disease. We have demonstrated that autophagy plays a key role in the development of AKI, but molecular mechanism responsible for autophagy activation in renal tubular epithelial cells (RTECs) during AKI remains largely unknown. Leucine-repeat kinase 2 (LRRK2) is an important regulator of autophagy, but its involvement in AKI keeps unknown. Our preliminary work suggests that during ischemic AKI, LRRK2 expression in renal tubular epithelial cells (RTECs) is upregulated, LRRK2 reduction impairs autophagy in RTECs and aggregates AKI. Therefore, we proposed that LRRK2 is a major regulator of autophagy in AKI. In this project, we will take advantage of established renal proximal tubule–specific LRRK2 knockout mice, LRRK2-depleted RTECs, autophagy reporter mouse model and specific LRRK2 kinase inhibitors to further verify the role of LRRK2 in the development of ischemic AKI, delineate the role and regulation of LRRK2 in RTEC autophagy during ischemic AKI, and decipher the underlying mechanism of LRRK2 induction during ischemic AKI. As a result, the findings will gain in-depth understanding of the mechanism of autophagy activation and AKI pathogenesis, and discover novel therapeutic targets.