Restoring mitochondrial superoxide levels with elamipretide (MTP-131) protects db/db mice against progression of diabetic kidney disease.

Exposure to chronic hyperglycemia due to diabetes mellitus can lead to the development and progression of diabetic kidney disease (DKD). We have recently reported that reduced superoxide production is associated with mitochondrial dysfunction in the kidneys of mouse models of type 1 DKD. We also demonstrated that humans with DKD have significantly reduced levels of mitochondrion-derived metabolites in their urine. Here, we examined renal superoxide production in a type 2 diabetes animal model, the db/db mouse, and the role of a mitochondrial-protectant, MTP-131 (also called elamipretide, SS-31, or Bendavia) in restoring renal superoxide production and ameliorating DKD. We found that18-week-old db/db mice have reduced renal and cardiac superoxide levels, as measured by dihydroethidium oxidation, and increased levels of albuminuria, mesangial matrix accumulation, and urinary hydrogen peroxide (H2O2). Administration of MTP-131 significantly inhibited the increases in albuminuria, urinary H2O2, and mesangial matrix accumulation in the db/db mice, and fully preserved levels of renal superoxide production in these mice. MTP-131 also reduced total renal lysocardiolipin (lysoCL) and major lysoCL subspecies, and preserved lysocardiolipin acyltransferase 1 (LCLAT1) expression in the db/db mice. These results indicate that in type 2 diabetes, DKD is associated with reduced renal and cardiac superoxide levels and that MTP-131 protects against DKD and preserves physiological superoxide levels possibly by regulating cardiolipin remodeling.