Figure 3

Activation of the immune and DNA damage response pathways in the kidney of BPS-TA mice. (A) BPS-TA mice on a high fat diet showed increased weight relative to chow fed BPS-TA. No significant differences in body weight were noted between BPS-TA, WT, and TRACK mice on a regular chow diet. (B) BPS-TA mice on a high fat diet showed a non-significant trend of increased fasting glucose levels relative to chow fed BPS-TA, confirming induction of metabolic stress. No significant differences in fasting glucose levels were noted between BPS-TA, WT, and TRACK mice on a regular chow diet. (C) Pathway Analysis of differentially expressed genes ‘Mitochondrial dysfunction’, ‘Oxidative Phosphorylation’, ‘Protein Ubiquitination Pathway’, ‘Phagosome Formation’, ‘Leukocyte extravasation Signaling’ and ‘Molecular Mechanisms of Cancer’ were the most significantly different pathways between WT and BPS-TA kidneys. The analysis was performed using Ingenuity Pathway Analysis software on RNAse dataset. Genes with (q < 0.05) were considered differentially expressed between BPS-TA (N = 4) and WT kidneys (N = 7) on a chow diet. (D) Promoter motif analysis indicated that Stat2, Atf4, Cebpb, Smad1 and Hif1a are significantly activated in BPS-TA kidneys as compared to WT kidneys. E) Significantly increased transcript levels of Trp53, Bbc3, Cdkn1a, Brca1, Top2a, Cdkn2a and Rad51, as measured by RNAseq. These results indicate that activation of the immune and DNA damage response pathways are potential mechanisms by which BPS-TA mice suppress carcinogenesis in the kidneys. Note that all BPS-TA mice evaluated were biallelic for each of the three transgenes.