SGLT2i reduces renal injury by improving mitochondrial metabolism and biogenesis

Area of Science:

• Nephrology
• Pharmacology
• Cell Biology

Background:

• Acute kidney injury (AKI) remains a significant clinical challenge with limited therapeutic options.
• Canagliflozin, an SGLT2 inhibitor, has demonstrated potential renal protective effects.
• Understanding the molecular mechanisms underlying canagliflozin's action in AKI is crucial.

Purpose of the Study:

• To investigate the therapeutic effects of canagliflozin on lipopolysaccharide-induced acute kidney injury (AKI) in a mouse model.
• To elucidate the underlying molecular pathways, particularly the role of mitochondrial function and the AMPK/PGC1α/NRF1 pathway.

Main Methods:

• Lipopolysaccharide (LPS) was used to induce AKI in mice, with co-administration of canagliflozin.
• In vitro studies utilized HK-2 cells treated with LPS and canagliflozin.
• Mitochondrial function, inflammatory markers, oxidative stress, and cell death were assessed.
• The role of the AMPKα1/PGC1α/NRF1 pathway was examined using pathway inhibitors and AMPKα1-knockout mice.

Main Results:

• Canagliflozin treatment significantly reduced blood urea nitrogen and serum creatinine levels, improving renal tubular structure in septic AKI mice.
• Canagliflozin suppressed inflammation, oxidative stress, and tubular cell death.
• In vitro, canagliflozin preserved mitochondrial function by restoring membrane potential, inhibiting ROS production, and normalizing respiratory complex activity.
• Canagliflozin activated the AMPKα1/PGC1α/NRF1 pathway, promoting mitochondrial biogenesis and protecting renal cells.

Conclusions:

• Canagliflozin demonstrates significant renoprotective effects in a model of septic AKI.
• The therapeutic benefits of canagliflozin are mediated through the activation of the AMPKα1/PGC1α/NRF1 pathway, leading to improved mitochondrial function and biogenesis.
• Canagliflozin represents a promising therapeutic strategy for treating septic AKI.