Transcription of MRPL12 regulated by Nrf2 contributes to the mitochondrial dysfunction in diabetic kidney disease

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.