TY - JOUR
T1 - NNMT inhibition counteracts tubular senescence and fibrosis in early stages of chronic kidney disease
AU - Chanvillard, Lucie
AU - Lantermans, Hildo C.
AU - Wall, Christopher
AU - Thevenet, Jonathan
AU - Butter, Loes M.
AU - Tauzin, Loic
AU - Claessen, Nike
AU - Christen, Stefan
AU - Holzwarth, James A.
AU - Karaz, Sonia
AU - Lassueur, Steve
AU - Lizzo, Giulia
AU - Sanchez-Garcia, José Luis
AU - Métairon, Sylviane
AU - Ferro, Valentina
AU - Moco, Sofia
AU - van Bommel, Erik J.M.
AU - van Baar, Michael J.B.
AU - Hesp, Anne C.
AU - van Raalte, Daniel H.
AU - Roelofs, Joris J.T.H.
AU - Neelakantan, Harshini
AU - Watowich, Stanley J.
AU - Sanders, Matthew J.
AU - Feige, Jerome N.
AU - Sorrentino, Vincenzo
AU - Tammaro, Alessandra
N1 - Publisher Copyright:
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2026/1/27
Y1 - 2026/1/27
N2 - Chronic kidney disease (CKD) is projected to become the fifth leading cause of mortality by 2040. Tubular senescence drives kidney fibrosis, but current treatments do not target senescent cells. Here, we identify nicotinamide-N-methyltransferase (NNMT) as a critical mediator of tubular senescence and kidney fibrosis. Human CKD microarrays link NNMT to senescence and fibrosis transcriptomic signatures, and diabetic kidney disease (DKD) biopsies show NNMT protein associating with p21, fibrosis, and kidney function decline. Spatial transcriptomics in human biopsies demonstrates that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Importantly, this pattern is conserved in aged and DKD mice, mimicking early-stage CKD features. Mechanistically, NNMT overexpression in tubular epithelial cells exacerbates senescence and partial epithelial-to-mesenchymal transition, while selective NNMT inhibition in senescent kidney cells, organoids, and in vivo is protective. Altogether, these findings position NNMT as a promising therapeutic target to reduce tubular senescence and fibrosis in early CKD.
AB - Chronic kidney disease (CKD) is projected to become the fifth leading cause of mortality by 2040. Tubular senescence drives kidney fibrosis, but current treatments do not target senescent cells. Here, we identify nicotinamide-N-methyltransferase (NNMT) as a critical mediator of tubular senescence and kidney fibrosis. Human CKD microarrays link NNMT to senescence and fibrosis transcriptomic signatures, and diabetic kidney disease (DKD) biopsies show NNMT protein associating with p21, fibrosis, and kidney function decline. Spatial transcriptomics in human biopsies demonstrates that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Importantly, this pattern is conserved in aged and DKD mice, mimicking early-stage CKD features. Mechanistically, NNMT overexpression in tubular epithelial cells exacerbates senescence and partial epithelial-to-mesenchymal transition, while selective NNMT inhibition in senescent kidney cells, organoids, and in vivo is protective. Altogether, these findings position NNMT as a promising therapeutic target to reduce tubular senescence and fibrosis in early CKD.
KW - aging
KW - chronic kidney disease
KW - CP: Metabolism
KW - diabetic kidney disease
KW - epigenetics
KW - kidney fibrosis
KW - kidney organoids
KW - nicotinamide-N-methyltransferase
KW - NNMT inhibitor
KW - S-adenosyl methionine
KW - tubular epithelial cell senescence
UR - https://www.scopus.com/pages/publications/105029047543
UR - https://www.scopus.com/pages/publications/105029047543#tab=citedBy
U2 - 10.1016/j.celrep.2025.116823
DO - 10.1016/j.celrep.2025.116823
M3 - Article
C2 - 41543936
AN - SCOPUS:105029047543
SN - 2211-1247
VL - 45
SP - 116823
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -