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Kidney Week

Abstract: TH-OR063

Short-Term Pulse Treatment with Nicotinamide Mononucleotide in Diabetic Nephropathy: Therapeutic Application of Metabolic Legacy Effect

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Yasuda, Itaru, Keio University, Tokyo, Japan
  • Hasegawa, Kazuhiro, Keio University, Tokyo, Japan
  • Ono, Takashi, Shionogi & Co., Ltd, Osaka, Japan
  • Wakino, Shu, Keio University, Tokyo, Japan
  • Itoh, Hiroshi, Keio University, Tokyo, Japan
Background

We previously demonstrated that the derangement of nicotinamide adenine dinucleotide (NAD+) metabolism and the inactivation of Sirt1, an NAD+-dependent deacetylation enzyme, initiated diabetic nephropathy (DN) (Nat Med, 2013). Sirt1 is activated by NAD+ precursor, nicotinamide mononucleotide (NMN). We tested short-term pulse treatment with NMN against DN.

Methods

We divided 8-week-old db/db and db/m mice into five groups: db/m + saline (db/m); db/db + saline (db/db); db/db + NMN 100 mg/kg (NMN100); db/db + NMN 300 mg/kg (NMN300); and db/db + NMN 500 mg/kg (NMN500). Short-term pulse treatment with NMN was performed via i.p. injection for two weeks. We terminated the treatment at 10 weeks of age and evaluated remote effects of NMN therapy at 10, 24, and 30 weeks of age. We also evaluated tissue NAD+ metabolite levels and the expressions of some enzymes of NAD+ metabolism, including Nampt that convert nicotinamide (NAM) into NMN and Nmnat1 that converts NMN into NAD+.

Results

At 24 weeks of age, db/db exhibited higher levels of HbA1c and albuminuria, as well as more foot process effacement and reduced expression of Sirt1 and Synaptopodin in renal histology as compared to those in the db/m. Although the HbA1c levels in the NMN500 and db/db were not different, NMN treatment resulted in lower albuminuria at even 14 and 20 weeks after the termination of therapy in a dose-dependent manner. NMN treatment ameliorated foot process effacement and preserved Sirt1 and Synaptopodin expressions. Renal NAD+ levels reduced with age in both db/m and db/db. In contrast, the NMN500 maintained NAD+ levels at 24 weeks of age. Nampt expression in the NMN500 was higher than those in the db/m and db/db. Nmnat1 expression was lower in the db/db than those in the db/m and NMN500, although Nmnat1 expression between the db/m and NMN500 was not different. These results indicated that the NMN treatment maintained renal NAD+ concentration by increasing Nampt expression and maintaining Nmnat1 expression.

Conclusion

Short-term pulse treatment with NMN at the early phase of DN had long-lasting renoprotective effects via restoration of NAD+ and preservation of Sirt1, Nampt, and Nmnat1 expressions independently of glycemic control. This intervention suggested the introduction of metabolic legacy effects during the course of DN.