Kidney Week

Abstract: SA-OR16

Loss of Functional SCO2 Attenuates Diabetic Kidney Disease in db/db Mice

Session Information

• Diabetic Kidney Disease: From Mechanisms to Treatment
  October 24, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Gujarati, Nehaben A., Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, United States

Nehaben A. Gujarati, PhD

Nehaben A. Gujarati completed her Bachelor’s in Pharmacy from India and earned her Master’s and Ph.D. at St. John’s University, New York. She is currently doing her postdoctoral with Dr. Sandeep K. Mallipattu in the division of Nephrology at Stony brook University-School of Medicine. Her research is mainly focused on understanding the role of mitochondria in diabetic kidney disease

• Leonardo, Alexandra R., Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, United States

Alexandra R. Leonardo,

• Vasquez, Jessica M., Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, United States

Jessica M. Vasquez,

• Mallipattu, Sandeep K., Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, United States

Sandeep K. Mallipattu,

Background

Synthesis of Cytochrome C Oxidase 2 (SCO2), a Cu²⁺ metallochaperone located in the inner mitochondrial membrane, is essential for the assembly of Complex IV (COX IV) of the electron transport chain, maintenance of the proton gradient, and redox signaling. Altered COX activity and reduced mitochondrial function have been reported in diabetic kidney disease (DKD), but the mechanism mediating this process remains to be explored.

Methods

db/db mice were bred with Sco2 mutant mice (E129K, most common human missense mutation in the Cu²⁺ binding domain) to generate Sco2^KO/KI;db/db and Sco2^KI/KI;db/db mice. Sco2^KO/KI, Sco2^KI/KI, db/db, and wildtype mice served as controls. All mice were euthanized at 24 weeks of age and assessed for functional and histological changes in the kidney.

Results

Data mining in Nephroseq showed that SCO2 expression was increased in micro-dissected glomeruli in human DKD kidney biopsies (Ju et al. 2013), which we confirmed by immunostaining in human kidney biopsies with DKD as compared to healthy donor nephrectomies. Since SCO2^-/- mice are embryonically lethal, we ascertained the role of mutant and heterozygous knockout SCO2 in DKD (SCO2^KI/KI, SCO2^KO/KI). As compared to db/db mice, SCO2^KO/KI;db/db and SCO2^KI/KI;db/db mice had a significant reduction in albuminuria, serum creatinine, glomerular hypertrophy, glomerular oxidative stress (8-oxoG staining) with an increase in podocyte number (WT1+ cells per glomerular cross-sectional area), synaptopodin expression, and overall survival. SCO2^KO/KI;db/db and SCO2^KI/KI;db/db mice also exhibited less glomerular endothelial injury with a decrease in glomerular capillary loop dilatation and a trend towards decrease in Icam and Vcam1 and an increase in Angpt1, Vegfa, Kdr and Klf2 expression as compared to db/db mice.

Conclusion

Loss of SCO2 and mutant SCO2 reduced glomerular endothelial injury, oxidative stress, and early diabetic injury in the kidney with improved mice survival in a murine model of DKD.

Funding

• NIDDK Support