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Download fileLoss of Functional SCO2 Attenuates Oxidative Stress in Diabetic Kidney Disease
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posted on 2021-10-26, 16:09 authored by Nehaben A. Gujarati, Alexandra R. Leonardo, Jessica M. Vasquez, Yiqing Guo, Bismark O. Frimpong, Elbek Fozilov, Monica P. Revelo, Ilse S. Daehn, John C. He, Daniel Bogenhagen, Sandeep K. MallipattuIncreased
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 this 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 (Sco2KO/KI, Sco2KI/KI),
with a functional loss of SCO2, in the progression of DKD using a murine model
of Type II Diabetes Mellitus, db/db mice. Diabetic Sco2KO/KI
and Sco2KI/KI hypomorphs exhibited a reduction in complex
IV activity, but an improvement in albuminuria, serum creatinine, and histomorphometric
evidence of early DKD as compared to db/db mice. Single-nucleus RNA sequencing
with gene set enrichment analysis of differentially expressed genes in the
endothelial cluster of Sco2KO/KI;db/db mice demonstrated an
increase in genes involved in VEGF-VEGFR2 signaling and reduced oxidative
stress as compared to db/db mice. These data suggest that reduced
complex IV activity due to a loss of functional SCO2 might be protective in GEnCs
in early DKD.