Kidney Week

Abstract: FR-PO274

Branched-Chain Amino Acids Drive Mesangial Expansion in Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Basic - 1
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Hagita, Junichiro, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Junichiro Hagita, MD

• Doke, Tomohito, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Tomohito Doke, MD, PhD

• Tsuboi, Toshiki, Shiritsu Yokkaichi Byoin, Yokkaichi, Mie, Japan

Toshiki Tsuboi, MD

• Tsubota, Shoma, Nagoya Daigaku Igakubu Seikagaku, Nagoya, Aichi, Japan

Shoma Tsubota, PhD

• Kato, Sawako, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Sawako Kato, MD, PhD

• Ito, Yasuhiko, Aichi Ika Daigaku Daigakuin Igaku Kenkyuka Igakubu, Nagakute, Aichi, Japan

Yasuhiko Ito, MD, PhD

• Ishimoto, Takuji, Aichi Ika Daigaku Daigakuin Igaku Kenkyuka Igakubu, Nagakute, Aichi, Japan

Takuji Ishimoto, MD, PhD

• Maruyama, Shoichi, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Shoichi Maruyama, MD, PhD

Background

The elevation of serum branched-chain amino acids (BCAAs) in diabetic patients has been observed for more than half a century, and it is reported to be associated with obesity and insulin resistance. We previously reported the unbiased metabolomics study identified significantly elevated levels of BCAAs in the kidneys and serum of db/db mice compared to db/m mice. Furthermore, these increases were reduced with SGLT2 inhibitor, Tofogliflozin. However, the contribution of BCAA to the development or progression of DKD has not been elucidated. This study is aimed to identify the effect of modulating BCAA catabolism on DKD.

Methods

The db/db and db/m mice were given 3,6-dichlorobenzo(b)thiophene-2-carboxylic acid (BT-2) (40mg/kg/day), a small molecule allosteric inhibitor of branched-chain α-keto acid dehydrogenase kinase (BDK) for 12 weeks. As an experimental model for BCAA overload, db/db and db/m mice were given a BCAA enrichment mixture (BCAAem) dissolved water for 8 weeks. The blood glucose levels, body weight, and food intake were regularly examined. Urinary albumin, serum leucine levels, and urinary thiobarbituric acid reactive substances (TBARS) were measured. PAS, PAM, and collagen IV staining were performed on FFPE sections.

Results

Body weight, blood glucose levels, albuminuria, and urinary TBARS levels were not significantly reduced in db/db mice treated with BT2 compared to db/db mice. However, serum leucine level, mesangial expansion, and collagen IV accumulation in the glomeruli were reduced in db/db mice treated with BT2. In contrast, the level of albuminuria and serum leucine were significantly increased in db/db mice treated with BCAAem with no change of urinary TBARS levels. Moreover, mesangial expansion in the glomeruli deteriorated in db/db mice treated with BCAAem.

Conclusion

Mesangial expansion induced by diabetes improved with the accompanying decrease in serum leucine concentration due to BT2 treatment. BCAA enrichment diet in diabetes deteriorates albuminuria and mesangial expansion. These findings suggest that circulating BCAA levels modify DKD progression. Intervention in BCAA metabolism may potentially prevent the progression of DKD.

Funding

• Commercial Support – Kowa Company, Ltd.