JCI Insight (Feb 2023)

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 M. Bachmann,
  • Dina Hofer,
  • Ellen Broeckx,
  • Jing Ying Ma,
  • Vinicius Carreira,
  • Tao Chen,
  • Nabil Azhar,
  • Romer A. Gonzalez-Villalobos,
  • Matthew Breyer,
  • Dermot Reilly,
  • Shannon Mullican,
  • Johan Auwerx

Journal volume & issue
Vol. 8, no. 3

Abstract

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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.

Keywords