NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury

Our understanding of how global changes in cellular metabolism contribute to human kidney disease remains incompletely understood. Here we show that nicotinamide adenine dinucleotide (NAD + ) deficiency drives mitochondrial dysfunction causing inflammation and kidney disease development. Using unbiased global metabolomics in healthy and diseased human kidneys, we identify NAD + deficiency as a disease signature. Furthermore using models of cisplatin- or ischaemia-reperfusion induced kidney injury in male mice we observed NAD + depletion Supplemental nicotinamide riboside or nicotinamide mononucleotide restores NAD + levels and improved kidney function. We find that cisplatin exposure causes cytosolic leakage of mitochondrial RNA (mtRNA) and activation of the cytosolic pattern recognition receptor retinoic acid-inducible gene I (RIG-I), both of which can be ameliorated by restoring NAD + . Male mice with RIG-I knock-out (KO) are protected from cisplatin-induced kidney disease. In summary, we demonstrate that the cytosolic release of mtRNA and RIG-I activation is an NAD + -sensitive mechanism contributing to kidney disease. Doke et al. show that NMN and NR supplementation has protective effects on kidney injury by preventing cisplatin-induced release of cytosolic mitochondrial RNA and subsequent activation of the RIG-I pathway and inflammation.