Kidney Week

Abstract: PO0722

Elucidation of Glomerular Hemodynamic Changes by SGLT-2 Inhibitors and ARBs in a Type 2 Diabetic Animal Model Using In Vivo Imaging

Session Information

• Diabetic Kidney Disease: Basic - II
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Wada, Yoshihisa, Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan

Yoshihisa Wada, MD

• Kidokoro, Kengo, Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan

Kengo Kidokoro,

• Umeno, Reina, Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan

Reina Umeno,

• Kondo, Megumi, Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan

Megumi Kondo,

• Kadoya, Hiroyuki, Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan

Hiroyuki Kadoya,

• Nagasu, Hajime, Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan

Hajime Nagasu,

• Sasaki, Tamaki, Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan

Tamaki Sasaki,

• Kashihara, Naoki, Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan

Naoki Kashihara,

Background

In recent clinical trials have shown that SGLT2 inhibitor (SGLT2i) inhibit the progression of diabetic kidney disease (DKD). We established the method for measuring single-nephron GFR (SNGFR) in mice by in vivo imaging and found that the adenosine / adenosine A1 receptor (A1aR) pathway in tubuloglomerular feedback (TGF) is involved in the pathogenesis of glomerular hyperfiltration (GH) in DKD using type1 diabetic animal model (Kidokoro K. et al. Circulation 2019). The mechanism of development of GH, and improvement of GH by SGLT2i is considered to be different in type 1 and type 2 DKD. However, the detailed regulatory mechanism of GFR has not been elucidated in type 2 DKD. We conducted experiments to elucidate the glomerular hemodynamic changes in type 2 diabetic animal model, using SGLT2i alone and in combination with RAAS inhibitor.

Methods

Zucker Lean (ZL) and Zucker Diabetic Fatty (ZDF) rats were used. Multi photon microscope was used to evaluate SNGFR, afferent arteriole (AA) and efferent arteriole (EA). The change in AA, EA, and SNGFR were observed every 30 minutes after SGLT2i administration. Furthermore, we investigated the involvement of the adenosine / A1aR pathway in type 2 diabetic animals using an A1aR antagonist (A1aRant). We made a SGLT2i + ARB combination group and measured AA, EA, and glomerular volume.

Results

ZDF showed a significant increase in blood glucose and urinary protein levels compared to ZL. SNGFR, AA and EA were significantly increased in ZDF compared to ZL, indicating GH. SGLT2i administration resulted in correction of AA hyperdilation and inhibition of GH. The inhibitory effect on hyperfiltration by SGLT2i was abolished by the concomitant use of A1aRant. There was no significant change about blood pressure, but urinary protein excretion was significantly suppressed by ARB treatment in ZDF. Glomerular volume was significantly increased, while there were no significant changes in AA and EA. SGLT2i ameliorated abnormal expansion of AA also in the presence of ARB, and no change in EA.

Conclusion

Our results showed that the regulation of AA vascular tonus by the adenosine/ A1aR pathway in TGF was involved in the GH in type 2 DKD.

Funding

• Commercial Support –