ヒストン脱メチル化の阻害は、培養ヒト近位尿細管上皮細胞において、Preiss-Handler経路を介してNAD合成を増強する

• Published in: 日本薬理学会年会要旨集 p. 1-B-P-051
• Main Authors: 小原, 真美, 平, 英一, 丸茂, 丈史, 村瀬, 真⼀, 近藤, ゆき子, 佐藤, 幸子, ハサン, アリフ
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: kidney; その他
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.96.0_1-B-P-051

Boosting nicotinamide adenine dinucleotide (NAD) production shows beneficial effects against diabetic kidney disease (DKD). However, the molecules that possess the therapeutic potential for increasing intracellular NAD-pool are not available. On the other hand, epigenetic modifiers are gradually gaining much interest in treating diseases such as DKD. KDM1A demethylates Lys 4 and Lys 9 of histone H3. We hypothesize that a selective KDM1A inhibitor, ORY-1001 may augment intracellular NAD synthesis in the DKD model. We induced hyperglycemic milieu in human proximal tubular epithelial HK2 cell-line using high glucose (4.5 g/L) in the presence or absence of ORY-1001 and compared the effect with their low glucose (1.0 g/L) containing counterparts. As anticipated, high glucose significantly reduced cellular NAD, while increasing NADH contents. The condition was restored by ORY-1001. To explore the underlying mechanisms, we thoroughly analyzed the mRNA expression profiles of the genes that are involved in NAD synthesis and metabolism. Consistent with the NAD production, NAPRT1 expression of the Preiss-Handler pathway was reduced by the high glucose, and treatment with ORY-1001 restored the expression. Moreover, a similar expression profile was found for PPARGC1a expression, a downstream effector of intracellular-NAD. Based on these findings, we presume that the KDM1A-inhibitor ORY-1001 has potential therapeutic benefits against DKD through augmenting NAD synthesis through upregulation of NAPRT1 of the Preiss-Handler pathway of NAD synthesis.