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

Satoshi Miyamoto, Guanshi Zhang, David Hall, Peter J. Oates, Soumya Maity, Muniswamy Madesh, Xianlin Han, Kumar Sharma

Research output: Contribution to journalArticle

Abstract

Exposure to chronic hyperglycemia because of diabetes mellitus can lead to development and progression of diabetic kidney disease (DKD). We 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 that 18-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 H2O2. Administration of MTP-131 significantly inhibited increases in albuminuria, urinary H2O2, and mesangial matrix accumulation in db/db mice and fully preserved levels of renal superoxide production in these mice. MTP-131 also reduced total renal lysocardiolipin and major lysocardiolipin subspecies and preserved lysocardiolipin acyltransferase 1 expression in 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.

Original languageEnglish
Pages (from-to)7249-7260
Number of pages12
JournalJournal of Biological Chemistry
Volume295
Issue number21
DOIs
Publication statusPublished - May 22 2020
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Restoring mitochondrial superoxide levels with elamipretide (MTP-131) protects db/db mice against progression of diabetic kidney disease'. Together they form a unique fingerprint.

  • Cite this