Figure 1. Strain-dependent responses to folic acid–induced kidney injury and their kinetics.

(A) The 7 selected mouse strains of the study, indicating the wild-derived strains (WSB/EiJ, CAST/EiJ, and PWK/PhJ) and the 2 strains from a different subspecies from Mus. musculus domesticus. Strain images are from ref. 9. (B) Experimental design of the study. Six male animals at 8 weeks of age were used per strain and condition. There were 5 experimental conditions: control (sodium bicarbonate) weeks 2 and 6, and folic acid weeks 1, 2, and 6 after injection. The total number of mice was 210, although only 202 reached the end of the experiment. At the end of the experiment, none of the conditions had fewer than 4 mice. (C) Principal component analysis of all measured phenotypes across all time points. The PCA is represented 3 times to highlight the time evolution of phenotypes. Loadings of selected kidney-related phenotypes are shown. (D) Comparison of the folic acid–induced effects on the plasma, urine, and morphological traits across strains and time points. Two-tailed Student t test P values were adjusted for multiple testing by Benjamin-Hochberg method (***P < 0.001, **P < 0.01, *P < 0.05). Cr_p, plasma creatinine; Cr_u, urine creatinine; Alb, urine albumin; BUN, blood urea nitrogen; SR, Sirius red staining quantification; TIMP-1, Tissue Inhibitor of Metalloproteases 1; GDF-15, Growth/Differentiation Factor-15; FGF-21, fibroblast growth factor 2; BUN/Cr_u, urea nitrog/creatinine ratio; Alb/Cr_u, urine albumin/creatinine ratio; Cr_u/p, Creatinine urine/plasma ratio. Values are Cohen’s effect sizes.