Abstract: SA-PO130
Nicotinamide N-methyltransferase (NNMT) Induction during AKI Reduces NAD+ and Durably Alters Global Gene Expression
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Clark, Amanda J., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Vu, Kyle Q., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Parikh, Samir M., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Background
NAD+ is a critical cofactor in cellular metabolism and is required for kidney tubular cell function. Reduced NAD+ abundance is a pathologic feature of both acute (AKI) and chronic kidney diseases (CKD). While NAD+ biosynthesis is suppressed in AKI, multiple studies demonstrate an upregulation of nicotinamide N-methyltransferse (NNMT) during injury. NNMT catalyzes the methylation of nicotinamide (NAM), the most significant NAD+ precursor. Methyl-NAM is permanently removed from NAD circulation. Further, via production of methyl-NAM, NNMT permanently removes circulating methyl groups. Thus, NNMT induction during AKI may represent an actionable target to increase NAD+ to reduce AKI severity and also a mechanism where AKI induces long-term changes in gene expression that could underly the AKI to CKD transition.
Methods
NNMT expression was measured using qPCR of mouse kidneys after AKI induced by cisplatin, folic acid, ischemic reperfusion injury (IRI), and lipopolysaccharide (LPS). A novel, inducible renal tubule specific NNMT overexpression mouse (iNephNNMT) was created - Pax8rtTA, tetOCre, fl-STOP-fl-NNMT. iNephNNMT mice had kidney function (GFR) estimated via measurement of serum creatinine after 4 weeks of overexpression followed by IRI or sham. Wild type mice induced with IRI were treated with NNMT inhibitors methyl-NAM and JBSNF followed by GFR estimation. RNASeq and ATACSeq were performed on kidneys from iNephNNMT mice and littermate controls.
Results
NNMT induction was a conserved feature across 4 distinct AKI mouse models: cisplatin, folic acid, IRI, and LPS. iNephNNMT mice exhibited reduced GFR at baseline as well as more severe injury after IRI compared to littermate controls. Two structurally unrelated NNMT inhibitors increased kidney NAD+ and protected against IRI. RNASeq and ATACSeq data from iNephNNMT kidneys demonstrated that NNMT overexpression increased chromatin accessibility at the native NNMT locus and led to sustained NNMT overexpression.
Conclusion
NNMT induction during AKI may be a conserved, maladaptive feature. Transient NNMT induction during periods of stress can lead to persistently increased NNMT expression, which in turn could perturb kidney metabolism towards greater injury susceptibility and fibrosis. Finally, NNMT may be an attractive therapeutic target in the AKI-to-CKD transition.
Funding
- NIDDK Support