Loss of Functional SCO2 Attenuates Oxidative Stress in Diabetic Kidney Disease

Increased oxidative stress in glomerular endothelial cells (GEnCs) contributes to early diabetic kidney disease (DKD). While mitochondrial respiratory complex IV activity is reduced in DKD, it remains unclear whether it is a driver or a consequence of oxidative stress in GEnCs. Synthesis of cytochrome C oxidase 2 (SCO2), a key metallochaperone in the electron transport chain, is critical to the biogenesis and assembly of subunits required for functional respiratory complex IV activity. Here, we investigated the effects of Sco2 hypomorphs (Sco2(KO/KI), Sco2(KI/KI)), with a functional loss of SCO2, in the progression of DKD by using a model of type 2 diabetes, db/db mice. Diabetic Sco2(KO/KI) and Sco2(KI/KI) hypomorphs exhibited a reduction in complex IV activity but an improvement in albuminuria, serum creatinine, and histomorphometric evidence of early DKD compared with db/db mice. Single-nucleus RNA sequencing using gene set enrichment analysis of differentially expressed genes in the endothelial cluster of Sco2(KO/KI);db/db mice demonstrated an increase in genes involved in VEGF-VEGFR2 signaling and reduced oxidative stress compared with db/db mice. These data suggest that reduced complex IV activity as a result of a loss of functional SCO2 might be protective in GEnCs in early DKD.

Automated summary

The study found that increased oxidative stress in glomerular endothelial cells (GEnCs) contributes to early diabetic kidney disease, but the loss of functional SCO2 leading to reduced complex IV activity may have a protective effect on GEnCs.