biostudies-literatureJones BANational Center for Advancing Translational SciencesNCATS NIH HHSNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNational Cancer InstituteNCI NIH HHSe181443https://www.ebi.ac.uk/biostudies/studies/S-EPMC11949063biostudies-literatureUnknown10(5)Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulated renal PPARα signaling and restored FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing showed that renal metabolic pathways were impaired in Alport mice and activated by NR in both sexes. ThesJCI insightNAD+ prevents chronic kidney disease by activating renal tubular metabolism.PMC11949063U54 DK137328R01DK127830R01 DK116567P30 CA051008P30CA051008F30 DK129003TL1TR001431P50DK133943U01 DK114923R01 DK127830P50 DK133943R01DK116567TL1 TR001431U01DK114923F30DK129003Eadon MTJain SSadiq ARosenberg AZYoshida TJones BAMyakala KSanto BALevi MYang XGisch DLMelo Ferreira RPanov JAllen KCTaranenko EKorolowicz KCheng YHWang XXfalseNAD+ prevents chronic kidney disease by activating renal tubular metabolism.Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulated renal PPARα signaling and restored FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing showed that renal metabolic pathways were impaired in Alport mice and activated by NR in both sexes. Thes2025-01-01T00:00:00Z2025 Mar2026-06-01T10:14:03.622Z2025-07-13T03:04:27.99ZS-EPMC119490634005982410.1172/jci.insight.181443