Nicotinamide N-Methyl Transferase as a Predictive Marker of Tubular Fibrosis in CKD

Qinglin Ye; Guiling Xu; Haizhen Huang; Shuting Pang; Boji Xie; Bingmei Feng; Peng Liang; Yijie Qin; Siji Li; Yin Luo; Chao Xue; Wei Li

doi:10.2147/IJGM.S420706

Nicotinamide N-Methyl Transferase as a Predictive Marker of Tubular Fibrosis in CKD

Int J Gen Med. 2023 Aug 7:16:3331-3344. doi: 10.2147/IJGM.S420706. eCollection 2023.

Authors

Qinglin Ye^#¹, Guiling Xu^#¹, Haizhen Huang^#¹, Shuting Pang¹, Boji Xie¹, Bingmei Feng¹, Peng Liang¹, Yijie Qin¹, Siji Li¹, Yin Luo¹, Chao Xue¹, Wei Li¹

Affiliation

¹ Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: 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.

Patients and methods: 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.

Results: 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).

Conclusion: 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.

Keywords: biomarker diagnosis; chronic kidney disease; nicotinamide N-methyl transferase; tubular fibrosis.