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

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. 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.

Automated summary

Doke et al. found that NMN and NR supplementation can protect against kidney injury caused by cisplatin, by inhibiting the release of mitochondrial RNA and the subsequent activation of the RIG-I pathway and inflammation. It is discovered that NAD(+) deficiency plays a role in mitochondrial dysfunction and the development of kidney disease. Supplementing with nicotinamide riboside or nicotinamide mononucleotide can restore NAD(+) levels and improve kidney function.