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Abstract: TH-PO857

Possible Role of Ketone Body Metabolism in SGLT2 Inhibitor-Mediated Renoprotection in High Fat Diet-Fed ApoE-Knockout Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Issei, Tomita, Shiga University of Medical Science, Otsu, Japan
  • Kume, Shinji, Shiga University of Medical Science, Otsu, Japan
  • Osawa, Norihisa, Shiga University of Medical Science, Otsu, Japan
  • Yamahara, Kosuke, Shiga University of Medical Science, Otsu, Japan
  • Yamahara, Mako, Shiga University of Medical Science, Otsu, Japan
  • Takeda, Naoko, Shiga University of Medical Science, Otsu, Japan
  • Kanasaki, Masami, Shiga University of Medical Science, Otsu, Japan
  • Mayoux, Eric, Boehringer-Ingelheim, Biberach an der Riss, Germany
  • Kaneko, Tatsuroh, Nippon Boehringer Ingelheim, Tokyo, Japan
  • Araki, Shin-ichi, Shiga University of Medical Science, Otsu, Japan
  • Maegawa, Hiroshi, Shiga University of Medical Science, Otsu, Japan
Background

A recent study showed that empagliflozin, a SGLT2 inhibitor, slowed renal function decline rate in diabetic patients regardless of proteinuria stage, suggesting that the treatment has a renoprotective property in diabetes. This animal study was aimed at revealing the renoprotective action of empagliflozin on atherosclerosis-related renal injury in diabetes, and a possible role of ketone body production in its renoprotective mechanism.

Methods

Study 1 examined the effect of oral administration of empagliflozin (30mg/kg) for 8 weeks on atherosclerosis and renoprotection in high fat diet (HFD)-fed ApoE knockout (ApoE-/-) mice, an animal model for atherosclerosis. Study 2 examined the effect of oral administration of 1,3-butanediol, a ketone body precursor, for 8 weeks on atherosclerosis and renoprotection in HFD-ApoE-/- mice.

Results

In Study 1, empagliflozin treatment significantly improved atherosclerosis in HFD-fed ApoE-/- mice. HFD-ApoE-/- mice showed significant increases in serum cystatin C levels without albuminuria, and F4/80-positive macrophage infiltration and fibronectin deposition in renal interstitium. These renal alterations were all significantly improved by the empagliflozin treatment, which was accompanied by significant increases in serum β-hydroxybutyric acid (β-OHB) levels.
In study 2, although the 1,3-BD treatment did not improved atherosclerosis in HFD-fed apoE-/- mice, similarly to the results from the empagliflozin study, the 1,3-BD treatment significantly improved serum cystatin C, and renal F4/80-positive macrophage infiltration and fibronectin deposition along with maintaining renal ATP contents in HFD-ApoE-/- mice. Finally, we confirmed that β-OHB supplementation inhibited apoptosis in the cultured proximal tubular cells stimulated with high glucose, saturated fatty acids and hypoxia.

Conclusion

Ketone body-derived energy supply to the hypoxic kidney could be a promising therapy for preventing renal dysfunction in diabetic kidney disease.