5/6 nephrectomy (5/6Nx) effect on the liver

Chronic renal failure (CRF) is associated with a decrease in drug metabolism. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYPs), but the mechanisms have been little explored. On the other hand, the expression of several CYP genes exhibits circadian rhythm. Here we report that downregulation of hepatic CYP3A11 (the murine homolog to human CYP3A4; the most decrease in 5/6Nx using microarray analysis) by suppressing the expression of clock gene; D-site binding protein (DBP). In vivo experiments, the mRNA levels of hepatic CYP3A11 exhibit circadian rhythm regulated by DBP and E4BP4, and significantly decreased in 5/6Nx. Microarray analysis revealed that the general transcription factors of CYP3A11 did not changed. However, DBP were downregulated and several CYP genes controlled by DBP also significantly decreased in 5/6Nx. These downregulations were not observed in angiotensin II type 1alpha receptor (AT II R1a) deficient 5/6Nx because serum TGF-beta was not upregulate. In vitro experiments, the RNA levels of CYP3A11 and DBP were downregulated in wild-type mouse hepatocytes incubated with serum from 5/6Nx, but did not changed in Id2 (-/-) hepatocytes. In fact, hepatic Id2 was upregulated and caused the downregulation of DBP in 5/6Nx. Hepatocyte treated with SD208 (TGF-beta receptor 1 selectivity inhibitor) recovered CYP3A11, DBP and Id2 to control levels. Furthermore, 5/6Nx treated with tranilast (inhibitor of TGF-beta production or isolation) or candesartan (ARBs) also recovered CYP3A11 levels. Our findings define that DBP has effects on downregulation of CYP3A11. In CRF conditions, TGF-beta is upregulated by angiotensin II receptor in renal and downregulates DBP and CYP3A11 levels mediated by Id2 in liver. Furthermore, downregulation of CYP3A11 can prevent by tranilast or candesartan. Differential gene expression between 5/6 nephrectomized and sham-operated mouse was measured on the liver.