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
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
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Research Article Nephrology

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

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.

Authors

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

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Figure 7

The transcript profile of the CC founder strains matches that of both CKD and AKI at week 1, while the PWK/PhJ and C57BL/6J strains match CKD at 6 weeks.

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The transcript profile of the CC founder strains matches that of both CK...
(A) Schematic of the approach. Gene expression signatures of human kidney diseases were obtained from public repositories (see Supplemental Table 2) and then compared with the mouse differentially expressed genes upon folic acid treatment. Both human and mouse data sets used a differentially expressed genes (DEGs) cutoff of |log2(fold change)| > 0.5 and FDR-corrected P < 0.05. Transcripts were considered overlapping if they varied in the same direction in mice and humans. Overlap percentage is “number overlapped transcripts”/“maximum possible overlap”, where the maximum possible overlap is the number of human and mouse DEGs — whichever is smallest. For each overlap, we performed a GSEA (see Supplemental Figure 8). (B) Overlap plot at week 1, exact numbers are indicated within each tile. Human kidney diseases overlap strongly with the response to folic acid in mice. This concordance was lost in most strains at week 6, except in the PWK/PhJ and C57BL/6J, which retained a large overlap (~20% genes) with human chronic kidney diseases. (C and D) Pie charts of selected significant gene sets among upregulated (C) or downregulated (D) transcripts. The size of each pie chart is log-proportional to the number of overlapped genes. The greatest overlaps involved an upregulation of immune-related transcripts and extracellular matrix components and a downregulation of mitochondrial and metabolic transcripts. This indicates a strong similarity between fibrogenesis, immune, and metabolic pathways implicated in mice and humans. At week 6, the inflammatory signature in the PWK/PhJ and C57BL/6J strains was similar to chronic human diseases but lost their similarities with acute kidney disease.