Toxicogenomics analysis correlates attenuation of Nrf2 function with renal toxicity in the rat

In order to gain understanding of mechanisms of chemically‐induced renal toxicity, we first curated 4 key biological pathways focused on kidney function and injury from a thorough review of the literature. Genes in these 4 pathways were then used to systematically query and analyze kidney data in DrugMatrix,® a large‐scale contextual microarray gene expression database of drug‐treated rat tissues. Data mining revealed a tightly‐clustered set of experiments, including treatments with compounds of well documented renal toxicity such as 4, 4′‐methylenedianiline, 6‐mercaptopurine, cerivastatin, rifampin and thalidomide. Pathway analysis revealed that genes involved in TGF‐β signaling, inflammation and oxidative stress responses are consistently upregulated by these compounds. However, heme‐oxygenase‐1 (HO‐1), a key cytoprotective mediator of oxidative stress response in kidney, was not up‐regulated, while many transcription factors that activate HO‐1 transcription were consistently up‐regulated. Further analysis revealed that this group of compounds induced the expression of an oxidative stress response suppressor, Bach1, and inhibited the function of Nrf2 which mediates the amplification of oxidative stress response in mammalian cells including the gene expression of HO‐1. Thus, Bach1 induction may be an important mechanism for compound‐induced renal dysfunction.