NNMT inhibition counteracts tubular senescence and fibrosis in early stages of chronic kidney disease.

Abstract

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.