Ye Qinglin, Xu Guiling, Huang Haizhen, Pang Shuting, Xie Boji, Feng Bingmei, Liang Peng, Qin Yijie, Li Siji, Luo Yin, Xue Chao, Li Wei
Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China.
Int J Gen Med. 2023 Aug 7;16:3331-3344. doi: 10.2147/IJGM.S420706. eCollection 2023.
Chronic kidney disease (CKD) progression is complex. There are not standardized methods for predicting the prognosis of CKD. Nicotinamide N-methyltransferase (NNMT) has been shown to be associated with renal fibrosis. This study aimed to validate NNMT as a prognostic biomarker of progressive CKD.
We explored the relationship between NNMT expression and CKD-related outcome variables using the NephroseqV5 and GEO databases. Additionally, a validation set of 37 CKD patients was enrolled to measure the correlation between NNMT expression levels and CKD outcomes. Furthermore, single-cell RNA sequencing data and the Human Protein Atlas were reanalyzed to investigate the expression specificity of NNMT in the kidney. Finally, to detect the status of NNMT expression with tubular fibrosis in vivo, we constructed a unilateral ureteral obstruction (UUO) mouse treated with an NNMT inhibitor.
Analyzing the datasets showed that NNMT was expressed mainly in proximal tubule compartments. And patients with high NNMT expression levels had a significantly lower overall survival rate compared to those with low NNMT expression levels (P = 0.013). NNMT was independent of prognosis factors in the multivariate Cox regression model, and the AUCs for CKD progression at 1, 3, and 5 years were 0.849, 0.775, and 0.877, respectively. Pathway enrichment analysis indicated that NNMT regulates the biological processes of tubulointerstitial fibrosis (TIF). In the validation group, NNMT levels were significantly higher in the CKD group combined with interstitial fibrosis. In vivo, NNMT was a high expression in the UUO group, peaking at postoperative day 21. Treatment with an NNMT inhibitor improved renal tubular interstitial fibrosis, and expression levels of FN, α-SMA, VIM, and TGF-β1 were decreased compared with UUO (P < 0.05).
NNMT was expressed mainly in tubular renal compartments, and associated with CKD prognosis. It holds potential as a diagnostic biomarker for tubular fibrosis in CKD.
慢性肾脏病（CKD）的进展较为复杂。目前尚无预测CKD预后的标准化方法。烟酰胺N-甲基转移酶（NNMT）已被证明与肾纤维化有关。本研究旨在验证NNMT作为进展性CKD的预后生物标志物。
我们使用NephroseqV5和GEO数据库探索NNMT表达与CKD相关结局变量之间的关系。此外，纳入37例CKD患者的验证集，以测量NNMT表达水平与CKD结局之间的相关性。此外，重新分析单细胞RNA测序数据和人类蛋白质图谱，以研究NNMT在肾脏中的表达特异性。最后，为了在体内检测NNMT表达与肾小管纤维化的状态，我们构建了用NNMT抑制剂治疗的单侧输尿管梗阻（UUO）小鼠。
分析数据集表明，NNMT主要在近端小管区室表达。与低NNMT表达水平的患者相比，高NNMT表达水平的患者总生存率显著更低（P=0.013）。在多变量Cox回归模型中，NNMT独立于预后因素，1年、3年和5年CKD进展的AUC分别为0.849、0.775和0.877。通路富集分析表明，NNMT调节肾小管间质纤维化（TIF）的生物学过程。在验证组中，合并间质纤维化的CKD组中NNMT水平显著更高。在体内，NNMT在UUO组中高表达，在术后第21天达到峰值。与UUO相比，用NNMT抑制剂治疗可改善肾小管间质纤维化，且FN、α-SMA、VIM和TGF-β1的表达水平降低（P<0.05）。
NNMT主要在肾小管区室表达，并与CKD预后相关。它有潜力作为CKD中肾小管纤维化的诊断生物标志物。
