Mitochondrial and NAD+ metabolism predict recovery from acute kidney injury in a diverse mouse population

• Published in: JCI insight 2023-02, Vol.8 (3)
• Main Authors: Morel, Jean-David, Sleiman, Maroun Bou, Li, Terytty Yang, von Alvensleben, Giacomo, Bachmann, Alexis M, Hofer, Dina, Broeckx, Ellen, Ma, Jing Ying, Carreira, Vinicius, Chen, Tao, Azhar, Nabil, Gonzalez-Villalobos, Romer A, Breyer, Matthew, Reilly, Dermot, Mullican, Shannon, Auwerx, Johan
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury; Animals; Humans; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; NAD; Nephrology; Renal Insufficiency, Chronic
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.164626

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.