Canagliflozin ameliorates renal oxidative stress and inflammation by stimulating AMPK-Akt-eNOS pathway in the isoprenaline-induced oxidative stress model

Sci Rep. 2020 Sep 4;10(1):14659. doi: 10.1038/s41598-020-71599-2.

Abstract

Diabetes is a leading cause of chronic kidney disease, and the high prevalence of sympathetic nervous system (SNS) hyperactivity in diabetic patients makes them further susceptible to SNS-mediated oxidative stress and accelerated kidney damage. Here, we investigated if canagliflozin can reverse isoprenaline (ISO)-induced renal oxidative damage in rats, a model that mimics SNS overstimulation-induced organ injuries in humans. We found that ISO administration elevates renal oxidative stress markers including malondialdehyde (MDA), advanced protein oxidation product (APOP), myeloperoxidase (MPO) and nitric oxide (NO), while depleting levels of endogenous antioxidants such as catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH). Strikingly, canagliflozin treatment of ISO-treated rats not only prevents elevation of oxidative stress markers but also rescues levels of depleted antioxidants. Our results also show that canagliflozin stimulates antioxidant/anti-inflammatory signaling pathways involving AMP-activated protein kinase (AMPK), Akt and eNOS, and inhibits iNOS and NADPH oxidase isoform 4 (NOX4), all of which are associated with oxidative stress and inflammation. Further, canagliflozin prevents ISO-induced apoptosis of kidney cells by inhibiting Bax protein upregulation and caspase-3 activation. Histological examination of kidney sections reveal that canagliflozin attenuates ISO-mediated increases in inflammatory cell infiltration, collagen deposition and fibrosis. Finally, consistent with these findings, canagliflozin treatment improves kidney function in ISO-treated rats, suggesting that the antioxidant effects may be clinically translatable.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Antioxidants / administration & dosage*
  • Canagliflozin / administration & dosage*
  • Cells, Cultured
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Isoproterenol / adverse effects*
  • Kidney Tubules / cytology
  • Male
  • Nitric Oxide Synthase Type III / metabolism*
  • Oxidative Stress / drug effects*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Long-Evans
  • Renal Insufficiency / chemically induced*
  • Renal Insufficiency / drug therapy*

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Canagliflozin
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Proto-Oncogene Proteins c-akt
  • AMP-Activated Protein Kinases
  • Isoproterenol