ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: SA-PO432

The Effect of Altered Branched-Chain Amino Acid (BCAA) Metabolism on Proteinuria and Mesangial Expansion in db/db Mice Treated with SGLT2 Inhibitor

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Hagita, Junichiro, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan
  • Tsuboi, Toshiki, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan
  • Tsubota, Shoma, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan
  • Kato, Sawako, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan
  • Ishimoto, Takuji, Aichi Ika Daigaku Daigakuin Igaku Kenkyuka Igakubu, Nagakute, Aichi, Japan
  • Ito, Yasuhiko, Aichi Ika Daigaku Daigakuin Igaku Kenkyuka Igakubu, Nagakute, Aichi, Japan
  • Doke, Tomohito, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan
  • Maruyama, Shoichi, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan
Background

The protective effect of SGLT2 inhibitors on diabetic kidney disease (DKD) have been reported, however, underlying molecular mechanism remains unclear. Unbiased kidney metabolomics and transcriptome analysis for kidneys treated with SGLT2 inhibitors have been warranted. Although lowering blood glucose levels is believed to have a protective effect on DKD, recent studies have shown that SGLT2 inhibitors modulate branched-chain amino acid (BCAA) transporter expression and mTORC1 function, indicating the role of BCAA metabolism in DKD.

Methods

SGLT2 inhibitor, Tofogliflozin (5mg/kg/day) was given to the db/m and db/db mice for 8 weeks. The blood glucose levels, body weight and food intake were regularly examined. Urinary albumin and creatinine levels were measured. PAS, PAM, and collagen IV were stained in kidney FFPE sections. LC-MS and RNA sequence for kidney tissues was performed. The phosphoS6 (pS6) was stained with Nephrin in frozen kidney tissue to see the mTORC1 activation in mesangial cells. Mes13 were incubated with BCAA, and the levels of collagen IV and proteins associated with mTORC1 activation pathway were examined.

Results

Blood glucose levels were significantly reduced in db/db mice treated with Tofogliflozin compared to db/db mice (p<0.01). The proteinuria, mesangial expansion, and collagen IV accumulation were reduced in db/db mice treated with Tofogliflozin. The unbiased metabolomics study identified significant changes in 68 metabolites of kidneys from db/db mice compared to db/m mice (p<0.05). Tofogliflozin reversed the changes in 15 out of 68 metabolites. In addition to the metabolites associated with glycolytic or polyol pathways, the levels of BCAA were significantly reduced in kidneys treated with Tofogliflozin (p<0.05). The higher levels of collagen IV were confirmed in MES13 treated with BCAA. The protein levels of phosphorylated forms of S6 (pS6) and S6K (pS6K) indicating mTORC1 activation. The higher expression of pS6 in the mesangial region of db/db mice and reduction of their levels in Tofogliflozin-treated db/db mice was confirmed.

Conclusion

Unbiased metabolomics analysis identified the reduction of BCAA levels in kidneys treated with an SGLT2 inhibitor. The higher BCAA levels promote mesangial expansion by modulating mTORC1 activation.

Funding

  • Commercial Support – Kowa Company, Ltd.