NNMT promotes tubular senescence and fibrosis in chronic kidney disease

Chanvillard, L., Lantermans, H., Wall, C., Thevenet, J., Butter, L., Tauzin, L., Claessen, N., Christen, S., Karaz, S., Lassueur, S., Izzo, G., Sanchez Garcia, J. L., Metairon, S., Holzwarth, J., Ferro, V., Moco, S., van Bommel, E., van Baar, M., Hesp, A., van Raalte, D., Roelofs, J., Sanders, M., Feige, J., Sorrentino, V., Tammaro, A.

Amsterdam UMC · biorxiv

Paper

Abstract

Chronic kidney disease (CKD) is a major global health issue, projected to become the fifth leading cause of mortality by 2040. Renal tubular cell senescence is a key driver of kidney fibrosis, the final manifestation of CKD. However, current treatment strategies, do not target senescent cells, as the underlying mechanisms driving this dysfunctional phenotype remain poorly described. Here, we identify nicotinamide-N-methyltransferase (NNMT), as a critical mediator of tubular senescence and fibrosis in CKD. Using human RNAseq profiles of CKD, we show that NNMT expression in the renal tubulointerstitium is strongly associated with CKD pathology and transcriptional signatures of cellular senescence. In human diabetic kidney disease biopsies, NNMT levels correlate with the senescence marker p21, kidney function decline, and fibrosis. Spatial transcriptomics further highlights that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Preclinical models of early-stage CKD, show upregulation of NNMT and association with senescence. Overexpression of NNMT in TGF-beta-stimulated tubular epithelial cells promotes senescence and partial epithelial-to-mesenchymal transition (EMT), while inhibition of NNMT in kidney cells and organoids is protective. Altogether, we identify NNMT as a novel therapeutic target in the early stages of CKD with the potential to reduce tubular senescence, fibrosis and significantly slow disease progression.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper addresses the role of NNMT in promoting tubular senescence and fibrosis in chronic kidney disease, which is a significant aspect of aging-related pathology. By identifying NNMT as a potential therapeutic target to mitigate senescence and fibrosis, the research contributes to understanding mechanisms that could slow disease progression, aligning with longevity research goals. However, while the findings are solid and provide a new avenue for treatment, they are more of an incremental advance rather than a groundbreaking discovery, hence the moderate impact score.

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