School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
Free Radic Biol Med. 2021 Feb 20;164:329-340. doi: 10.1016/j.freeradbiomed.2021.01.004. Epub 2021 Jan 11.
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Increasing evidences suggested that DKD correlates more closely to mitochondrial dysfunction than to hyperglycemia. Our previous study has reported that mitochondrial ribosomal protein L7/L12 (MRPL12) could positively control the mitochondrial oxidative phosphorylation (OXPHOS) and mtDNA copy number. The present study further investigated the role of MRPL12 in mitochondrial dysfunction of DKD. Using a mass spectrometry-based proteomics and immunohistochemistry, we found that MRPL12 underwent significant decreases in diabetic kidneys. Moreover, decreased expression of MRPL12 was associated with reduced mitochondrial OXPHOS in proximal tubular epithelial cells (PTECs) and overexpression of MRPL12 could alleviated the impairment of OXPHOS induced by long term high glucose. We further explored the upstream mechanism and identified nuclear factor erythroid 2-related factor 2 (Nrf2) as a potential transcription factor for MRPL12. Nrf2 changes consistently with MRPL12 in DKD and correlates with alterations of mitochondrial function, fibrosis and apoptosis of PTECs treated with high glucose challenge. Thus, the role of MRPL12 in the maintenance of mitochondrial function in DKD may be regulated by Nrf2, and provides new potential therapeutic targets for DKD.
糖尿病肾病（DKD）是慢性肾脏病（CKD）和终末期肾病（ESRD）的主要原因。越来越多的证据表明，DKD 与线粒体功能障碍的相关性比与高血糖更为密切。我们之前的研究报告称，线粒体核糖体蛋白 L7/L12（MRPL12）可以积极控制线粒体氧化磷酸化（OXPHOS）和 mtDNA 拷贝数。本研究进一步探讨了 MRPL12 在 DKD 中线粒体功能障碍中的作用。通过基于质谱的蛋白质组学和免疫组织化学，我们发现糖尿病肾脏中 MRPL12 显著减少。此外，MRPL12 的表达降低与近端肾小管上皮细胞（PTEC）中线粒体 OXPHOS 的减少有关，而过表达 MRPL12 可以减轻长期高葡萄糖诱导的 OXPHOS 损伤。我们进一步探讨了上游机制，并确定核因子红细胞 2 相关因子 2（Nrf2）为 MRPL12 的潜在转录因子。在 DKD 中，Nrf2 的变化与 MRPL12 一致，并与高葡萄糖处理后 PTEC 中线粒体功能、纤维化和细胞凋亡的改变相关。因此，MRPL12 在 DKD 中线粒体功能维持中的作用可能受 Nrf2 调节，为 DKD 提供了新的潜在治疗靶点。
