Abcc4 mRNA expression was unchanged in db/db females, but was significantly increased, by almost 3-fold in kidneys of db/db male mice, as compared to that detected in male C57BKS mice. Also, basal expression of Abcc4 mRNA as well as protein in female kidney was almost 3-fold higher than that expressed male kidney. Abcc2 mRNA expression in kidney did not differ between db/db and C57BKS mice for either gender (data not shown). Db/db mice exhibit altered nuclear receptor and receptor target gene expression The relative expression of the transcription C188-9 in vivo factor, nuclear factor E2 related factor 2 (Nrf2), as well as nuclear hormone receptors peroxisome proliferator activated receptor

alpha (Ppar-α), constitutive androstane receptor (Car), farnesoid-X-receptor (Fxr) and pregnane-X-receptor (Pxr) mRNA expression was quantified in livers of db/db mice (Figure 7). In both male and female db/db mice, Nrf2 mRNA expression was significantly increased compared to C57BKS controls. Glutamate cysteine ligase (Gclc), 17DMAG a Nrf2 target gene, was correspondingly increased

in livers of db/db mice. Ppar-α, and its target gene Cyp4a14 mRNA expression were also higher in male and female db/db mice as compared to C57BKS mice. Similarly, Car and Cyp2b10 expression also increased in male db/db mice as compared to C57BKS. Female db/db mice also displayed increased Cyp2b10, however, Car was unchanged. Pxr mRNA expression was not altered, however, its target Cyp3a11 expression was Wilson disease protein increased in db/db males. Similarly, Fxr mRNA did not increase significantly, however, one of its target genes, small heterodimer

partner (Shp) was increased in db/db females compared to C57BKS females. Figure 7 Trascription factor Nrf2, and nuclear receptor Ppar-α, Fxr, Pxr, Car and their target genes mRNA expression in livers of C57BKS and db/db mice. Messenger RNA expression of Nrf2, Ppar-α, Fxr, Pxr, Car, Gclc, Cyp4a14, Cyp2b10, Cyp3a11 and Shp was quantified. Total RNA was isolated from livers of adult db/db and C57BKS mice, and mRNA expression was quantified using the branched DNA signal amplification assay. The data plotted as average RLU per 10 μg total RNA ± SEM. Asterisks (*) represent a statistically significant expression difference between db/db mice and C57BKS mice of the same gender (p≤0.05). Number signs (#) represent a statistically significant expression difference between male and female db/db mice or male and female C57BKS mice. Nrf2 and its target gene Gclc display increase in male as well as female db/db mice, as compared to respective C57BKS controls. Similarly, Ppar-α and Cyp4a14 expression also increased in db/db mice. Car expression was increased in male db/db mice, and its target gene Cyp2b10 expression was also increased in male as well as female db/db mice.