Compensation is a physiological response that occurs during chemical exposure to maintain homeostasis. Since compensatory responses are not considered adverse effects, it is important to understand its detailed mechanisms. Although the kidney is a major target organ for toxicity, there is controversy whether the compensation is contributed by hyperplasia or by hypertrophy, and there is limited information to apply for chemical risk assessment. In this study, compensatory mechanisms of the kidney were investigated in unilateral nephrectomy (UNx) model using adult male and female F344 rats. In residual kidneys of male and female rats after UNx, 5-bromo-2'-deoxyuridine-labeling indices and mRNA expression of cell cycle-related genes were increased, while there were no fluctuations in mRNA expression of transforming growth factor-β1, which contributes to hypertrophy in renal tubules. Pathway analysis using microarray data for mRNA revealed forkhead box M1 (FOXM1) as an upstream regulator of cell proliferation in residual kidneys of both sexes. Microarray for microRNAs (miRNAs) demonstrated that 9 miRNAs were downregulated in residual kidneys, and mRNA/miRNA integrated analysis indicated that miRNAs were associated with the expression of factors downstream of FOXM1. Overall results suggested that FOXM1-mediated hyperplasia contributed to compensatory mechanisms in the kidney and that miRNAs regulated downstream FOXM1 signaling. These results will be beneficial for evaluating nephrotoxicity in chemical risk assessment and for developing new biomarkers to predict nephrotoxicity.
