Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China.
Metabolism. 2019 Sep;98:95-103. doi: 10.1016/j.metabol.2019.06.008. Epub 2019 Jun 18.
Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Vitamin D receptor (VDR) belongs to the nuclear receptor superfamily and exerts a renoprotective effect through inhibiting fibrosis. Microtubule-associated protein 1 light chain 3 (LC3), a key regulator of autophagy, is abundant in the nucleus, although its primary function is in the cytoplasm. The role of nuclear LC3 and the mechanism by which LC3 shuttles between the cytoplasm and nucleoplasm has not been fully elucidated. We found that LC3 binds to VDR in an LC3-interacting region (LIR)-independent manner and promotes the nuclear translocation of VDR. Further study indicated that LC3 promotes the formation of the VDR:retinoid X receptor (RXR) heterodimer and inhibits fibrogenic genes expression in HK-2 cells induced by high glucose. Our result demonstrates that LC3 is a negative regulator of high glucose-induced fibrogenic genes expression through its ability to promote VDR signaling.
糖尿病肾病（DN）是终末期肾病（ESRD）的主要原因。维生素 D 受体（VDR）属于核受体超家族，通过抑制纤维化发挥肾保护作用。微管相关蛋白 1 轻链 3（LC3）是自噬的关键调节因子，尽管其主要功能在细胞质中，但在核内也大量存在。核 LC3 的作用以及 LC3 在细胞质和核质之间穿梭的机制尚未完全阐明。我们发现 LC3 以不依赖于 LC3 相互作用区域（LIR）的方式与 VDR 结合，并促进 VDR 的核易位。进一步的研究表明，LC3 促进 VDR:视黄醇 X 受体（RXR）异二聚体的形成，并抑制高糖诱导的 HK-2 细胞中成纤维基因的表达。我们的结果表明，LC3 通过促进 VDR 信号转导，成为高糖诱导的成纤维基因表达的负调节剂。
