Mouse genetic background controls the severity of kidney injury

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. Overall design: This study used 7 domesticated (C57BL/6J, DBA/2J, A/J, 129S1/SvlmJ,WSB/EiJ) or wild-derived (CAST/EiJ, PWK/PhJ) inbred mouse strains drawn from founders the well-characterized BXD and collaborative cross panels, that are well known for their diversity in genetics, as well as in molecular and cardio-metabolic phenotypes. Mouse strains were imported from Charles River and bred at the École Polytechnique Fédérale de Lausanne (EPFL) animal facility for more than two generations before incorporation into the study. All research was approved by the Swiss cantonal veterinary authorities of Vaud under license 30759.The mice were fed a chow diet (Harlan 2018 (6% kCal of fat, 20% kCal of protein, and 74% kCal of carbohydrates). Mice were housed at 2-4 animals per cage under 12 hours light/dark cycle, with ad libitum access to food and water at all times. Body weight was measured weekly from 8 weeks of age until killing. We examined 7 mouse inbred strains. At 9 weeks of age, 3 groups of mice were treated with 125mg/kg of folic acid in 3M sodium bicarbonate and two groups with bicarbonate alone (vehicle controls). Strains were entered into each group randomly, then observed daily to monitor their health. The mice were scored weekly according to body weight/food intake, Coat condition, movement and signs of pain. Mice scoring above 1 were monitored three times a week and mice scoring above 2 were monitored daily. Mice with a score of 3 were sacrificed. Mice were sacrificed at week 1,2 and 6 (folic acid treated) or weeks 2 and 6 (controls). The sacrifices took place from 8:30 a.m. until 12 a.m., with isoflurane anesthesia followed by a complete blood draw (~1 mL) from the vena cava, followed by perfusion with phosphate-buffered saline. The kidney was collected and flash-frozen in liquid nitrogen