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Kidney Week

Abstract: PO0715

Investigation of the Renoprotective Effect of SGLT-2 Inhibitors Focused on Glomerular Hyperfiltration and Oxidative Stress in Mice with Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Kondo, Megumi, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Kidokoro, Kengo, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Kadoya, Hiroyuki, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Sasaki, Tamaki, Kawasaki Medical School, Kurashiki, Okayama, Japan
  • Kashihara, Naoki, Kawasaki Medical School, Kurashiki, Okayama, Japan

In recent clinical trials, sodium-glucose cotransporter 2 (SGLT2) inhibitors slowed the progression of DKD compared with placebo. One of the main mechanisms for the renoprotective effect of SGLT2 inhibitors in DKD is the improvement of glomerular hyperfiltration. We previously demonstrated that the adenosine/adenosine A1 receptor pathway played a pivotal role in the tubulo-glomerular feedback system in type 1 diabetic model mice (Circulation, 2019). We also reported that increased glomerular oxidative stress was involved in the progression of albuminuria in DKD (Diabetologia, 2010). Loss of tetrahydrobiopterin (BH4), which is a cofactor of eNOS, causes uncoupling of endothelial nitric oxide (NO) synthase (eNOS), resulting in increased superoxide production in DKD (AJPRP, 2005; JASN, 2013). In this study, we explored the renal protective effects of SGLT2 inhibition, with a focus on glomerular hemodynamics and glomerular oxidative stress.


We used db/db mice as a model for type 2 diabetes. Mice were treated with canagliflozin (CANA; 10mg/kg) for 8 weeks. We evaluated the change of single nephron glomerular filtration rate (SNGFR) and glomerular permeability of albumin using in vivo multiphoton microscopy imaging. Glomerular reactive oxygen species (ROS) and NO production were evaluated by ex vivo study. Low temperature sulfate-polyacrylamide gel electrophoresis was performed for detection of eNOS uncoupling. In addition, tomato lectin staining was carried out to estimate the vascular endothelial damage.


Glomerular hyperfiltration and urinary albumin excretion in db/db mice was ameliorated by CANA treatment. Accelerated ROS production and diminished bioavailable NO caused by eNOS uncoupling in glomeruli were observed in db/db mice. CANA suppressed eNOS uncoupling and improved ROS/NO imbalance via maintenance of BH4. CANA inhibited degradation of endothelial surface layer due to increased glomerular oxidative stress.


SGLT2 inhibitor restore glomerular hyperfiltration in DKD. Simultaneously, intraglomerular ROS/NO imbalance via eNOS uncoupling was improved by SGLT2 inhibitor.


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