Nephrology Division, Department of Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
PeerJ. 2023 Nov 8;11:e16301. doi: 10.7717/peerj.16301. eCollection 2023.
Chronic kidney disease (CKD) is a significant global health issue characterized by progressive loss of kidney function. Renal interstitial fibrosis (TIF) is a common feature of CKD, but current treatments are seldom effective in reversing TIF. Nicotinamide N-methyltransferase (NNMT) has been found to increase in kidneys with TIF, but its role in renal fibrosis is unclear.
Using mice with unilateral ureteral obstruction (UUO) and cultured renal interstitial fibroblast cells (NRK-49F) stimulated with transforming growth factor-β1 (TGF-β1), we investigated the function of NNMT and .
We performed single-cell transcriptome sequencing (scRNA-seq) on the kidneys of mice and found that NNMT increased mainly in fibroblasts of UUO mice compared to sham mice. Additionally, NNMT was positively correlated with the expression of renal fibrosis-related genes after UUO injury. Knocking down NNMT expression reduced fibroblast activation and was accompanied by an increase in DNA methylation of p53 and a decrease in its phosphorylation.
Our findings suggest that chronic kidney injury leads to an accumulation of NNMT, which might decrease p53 methylation, and increase the expression and activity of p53. We propose that NNMT promotes fibroblast activation and renal fibrosis, making NNMT a novel target for preventing and treating renal fibrosis.
慢性肾脏病（CKD）是一种严重的全球健康问题，其特征是肾功能逐渐丧失。肾间质纤维化（TIF）是 CKD 的一个常见特征，但目前的治疗方法很少能有效地逆转 TIF。烟酰胺 N-甲基转移酶（NNMT）已被发现存在于 TIF 的肾脏中，但它在肾纤维化中的作用尚不清楚。
我们使用单侧输尿管梗阻（UUO）小鼠和转化生长因子-β1（TGF-β1）刺激的培养的肾间质成纤维细胞（NRK-49F）进行研究，以探讨 NNMT 的功能。
我们对 UUO 小鼠和假手术对照小鼠的肾脏进行了单细胞转录组测序（scRNA-seq），结果发现与 sham 小鼠相比，NNMT 在 UUO 小鼠的成纤维细胞中表达增加。此外，在 UUO 损伤后，NNMT 与肾纤维化相关基因的表达呈正相关。敲低 NNMT 表达可减少成纤维细胞激活，同时增加 p53 的 DNA 甲基化和减少其磷酸化。
我们的研究结果表明，慢性肾损伤导致 NNMT 积累，可能降低 p53 的甲基化，增加 p53 的表达和活性。我们提出 NNMT 促进成纤维细胞激活和肾纤维化，使 NNMT 成为预防和治疗肾纤维化的新靶点。
