Mitochondrial and NAD+ metabolism predict recovery from acute kidney injury in a diverse mouse population
Jean‐David Morel, Maroun Bou Sleiman, Terytty Yang Li, Giacomo von Alvensleben, Alexis Bachmann, Dina Hofer, Ellen Broeckx, Jing Ying, Vinicius Carreira, Tao Chen, Nabil Azhar, Romer A. González-Villalobos, Matthew D. Breyer, Dermot F. Reilly, Shannon E. Mullican, Johan Auwerx
Abstract
Acute kidney failure and chronic kidney disease are global health issues steadily rising in incidence and prevalence. Animal models on a single genetic background have so far failed to recapitulate the clinical presentation of human nephropathies. Here, we used a simple model of folic acid-induced kidney injury in 7 highly diverse mouse strains. We measured plasma and urine parameters, as well as renal histopathology and mRNA expression data, at 1, 2, and 6 weeks after injury, covering the early recovery and long-term remission. We observed an extensive strain-specific response ranging from complete resistance of the CAST/EiJ to high sensitivity of the C57BL/6J, DBA/2J, and PWK/PhJ strains. In susceptible strains, the severe early kidney injury was accompanied by the induction of mitochondrial stress response (MSR) genes and the attenuation of NAD+ synthesis pathways. This is associated with delayed healing and a prolonged inflammatory and adaptive immune response 6 weeks after insult, heralding a transition to chronic kidney disease. Through a thorough comparison of the transcriptomic response in mouse and human disease, we show that critical metabolic gene alterations were shared across species, and we highlight the PWK/PhJ strain as an emergent model of transition from acute kidney injury to chronic disease.