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Mouse genetic background controls the severity of kidney injury

ABSTRACT: Acute kidney failure and chronic kidney disease are global health issues steadily rising in incidence and prevalence. Animal models are critically needed to better understand these diseases and develop new therapies. These models are typically restricted to a single genetic background, thus fail to recapitulate the hallmarks of human nephropathies and the diversity of their associated clinical presentations. Here, we used a simple model of folic acid-induced kidney injury in 7 highly diverse mouse strains. We measure plasma and urine parameters, as well as renal histopathology and mRNA expression data at 1-, 2- and 6-weeks after folic acid administration, covering the early response and subsequent recovery from injury. We observe 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. We show that in these susceptible strains, the severe early kidney injury is accompanied by the induction of mitochondrial stress genes, which is associated with delayed healing and a prolonged inflammatory and adaptive immune responses 6 weeks after the insult, heralding a transition to chronic kidney disease. Our data catalogue the variability in predisposition to acute kidney injury, recovery, and transition to chronic kidney disease in laboratory strains, enabling better selection of mouse strains to study kidney disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE222570 | GEO | 2023/01/11

REPOSITORIES: GEO

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Project description:The collaborative cross (CC) founder strains include five classical inbred laboratory strains (129S1/SvlmJ, A/J, C57BL/6J (B6), NOD/ShiLtJ, and NZO/HILtJ) and three wild-derived strains (CAST/EiJ, PWK/PhJ (PWK) and WSB/EiJ) The strains encompass 89% of the genetic diversity available in Mus musculus and about 10 to 20 times more genetic diversity than found in Homo sapiens. For more than 60 years the B6 strain has been used as the model strain for high ethanol preference/high consumption. However, another one of the CC founder strains, PWK, was identified as a high ethanol preference/high consumption strain. The current study determined how the transcriptomes of the B6 and PWK strains differed from the 6 low preference CC strains across 3 nodes of the brain addiction circuit. RNA-Seq data were collected from the central nucleus of the amygdala, the nucleus accumbens core and the prelimbic cortex. Differential expression (DE) analysis was performed in each of these brain regions for all 28 possible pairwise comparisons of the CC founder strains. Unique genes for each strain were identified by selecting for genes that differed significantly (false discovery rate (FDR) < 0.05) from all other strains in the same direction. B6 was identified as the most distinct inbred laboratory strain, having the highest number of total differently expressed genes (DEGs) and DEGs with high log fold change, and unique genes compared to other CC strains. Less than 50 unique DEGs were identified in common between B6 and PWK within all three brain regions, indicating the strains potentially represent two distinct genetic signatures for risk for high ethanol-preference. 238 DEGs were found to be commonly different between B6, PWK and the average expression of the remaining CC strains within all three regions. The commonly different up-expressed genes were significantly enriched (FDR < 0.001) among genes associated with neuroimmune function. These data compliment the observation that neuroimmune signaling is key to understanding alcohol use disorder and and support use of these 8 strains and the highly heterogeneous mouse populations derived from them to identify alcohol-related brain mechanisms and treatment targets.

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Mouse genetic background controls the severity of kidney injury

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