Wang Yanyan, Xu Yanan, Wang Qingzhu, Guo Feng, Song Yi, Fan Xunjie, Shao Mingwei, Chen Duo, Zhang Wei, Qin Guijun
The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China.
Eur J Pharmacol. 2023 Nov 5;958:176042. doi: 10.1016/j.ejphar.2023.176042. Epub 2023 Sep 3.
Mitophagy, a mechanism of self-protection against oxidative stress, plays a critical role in podocyte injury caused by diabetic kidney disease (DKD). Sulforaphane (SFN), an isothiocyanate compound, is a potent antioxidant that affords protection against diabetes mellitus-mediated podocyte injury. However, its role and underlying mechanism in DKD especially in diabetic podocytopathy is not clearly defined. In the current study, we demonstrated SFN remarkably activated mitophagy in podocytes, restored urine albumin to creatinine ration, and prevented the glomerular hypertrophy and extensive foot process fusion in diabetic mice. Simultaneously, nephroprotective effects of SFN on kidney injury were abolished in podocyte-specific Nuclear factor erythroid 2-related factor 2 (Nrf2) conditional knockout mouse (cKO), indicating that SFN alleviating DM-induced podocyte injury dependent on Nrf2. In vitro study, supplement with SFN augmented the expression of PTEN induced kinase 1(PINK1) and mediated the activation of mitophagy in podocytes treated with high glucose. Further study revealed that SFN treatment enabled Nrf2 translocate into nuclear and bind to the specific site of PINK1 promoter, ultimately reinforcing the transcription of PINK1. Moreover, SFN failed to confer protection to podocytes treated with high glucose in presence of PINK1 knockdown. On the contrary, exogenous overexpression of PINK1 reversed mitochondrial abnormalities in Nrf2 cKO diabetic mice. In conclusion, SFN alleviated podocyte injury in DKD through activating Nrf2/PINK1 signaling pathway and balancing mitophagy, thus maintaining the mitochondrial homeostasis.
线粒体自噬是一种针对氧化应激的自我保护机制，在糖尿病肾病（DKD）所致的足细胞损伤中起关键作用。萝卜硫素（SFN）是一种异硫氰酸酯化合物，是一种有效的抗氧化剂，可预防糖尿病介导的足细胞损伤。然而，其在DKD尤其是糖尿病足细胞病变中的作用及潜在机制尚不清楚。在本研究中，我们证明SFN可显著激活足细胞中的线粒体自噬，恢复尿白蛋白与肌酐比值，并预防糖尿病小鼠的肾小球肥大和广泛的足突融合。同时，在足细胞特异性核因子红细胞2相关因子2（Nrf2）条件性敲除小鼠（cKO）中，SFN对肾损伤的肾保护作用消失，这表明SFN减轻糖尿病诱导的足细胞损伤依赖于Nrf2。体外研究表明，补充SFN可增加PTEN诱导激酶1（PINK1）的表达，并介导高糖处理的足细胞中线粒体自噬的激活。进一步研究发现，SFN处理可使Nrf2易位至细胞核并与PINK1启动子的特定位点结合，最终增强PINK1的转录。此外，在敲低PINK1的情况下，SFN未能对高糖处理的足细胞提供保护。相反，外源性过表达PINK1可逆转Nrf2 cKO糖尿病小鼠的线粒体异常。总之，SFN通过激活Nrf2/PINK1信号通路和平衡线粒体自噬，减轻DKD中的足细胞损伤，从而维持线粒体稳态。
