The significance of NAD + metabolites and nicotinamide N-methyltransferase in chronic kidney disease

Rina Takahashi, Takeshi Kanda, Motoaki Komatsu, Tomoaki Itoh, Hitoshi Minakuchi, Hidenori Urai, Tomohiro Kuroita, Shuhei Shigaki, Tasuku Tsukamoto, Naoko Higuchi, Minoru Ikeda, Risa Yamanaka, Norito Yoshimura, Takashi Ono, Hideo Yukioka, Kazuhiro Hasegawa, Hirobumi Tokuyama, Shu Wakino, Hiroshi Itoh

Research output: Contribution to journalArticlepeer-review

Abstract

Dysregulation of nicotinamide adenine dinucleotide (NAD +) metabolism contributes to the initiation and progression of age-associated diseases, including chronic kidney disease (CKD). Nicotinamide N-methyltransferase (NNMT), a nicotinamide (NAM) metabolizing enzyme, regulates both NAD + and methionine metabolism. Although NNMT is expressed abundantly in the kidney, its role in CKD and renal fibrosis remains unclear. We generated NNMT-deficient mice and a unilateral ureter obstruction (UUO) model and conducted two clinical studies on human CKD to investigate the role of NNMT in CKD and fibrosis. In UUO, renal NNMT expression and the degraded metabolites of NAM increased, while NAD + and NAD + precursors decreased. NNMT deficiency ameliorated renal fibrosis; mechanistically, it (1) increased the DNA methylation of connective tissue growth factor (CTGF), and (2) improved renal inflammation by increasing renal NAD + and Sirt1 and decreasing NF-κB acetylation. In humans, along with CKD progression, a trend toward a decrease in serum NAD + precursors was observed, while the final NAD + metabolites were accumulated, and the level of eGFR was an independent variable for serum NAM. In addition, NNMT was highly expressed in fibrotic areas of human kidney tissues. In conclusion, increased renal NNMT expression induces NAD + and methionine metabolism perturbation and contributes to renal fibrosis.

Original languageEnglish
Article number6398
JournalScientific reports
Volume12
Issue number1
DOIs
Publication statusPublished - 2022 Dec
Externally publishedYes

ASJC Scopus subject areas

  • General

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