N. Karimian Pour, M. Piquette-Miller; Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
Background: Transporters expressed in the kidney can impact the renal clearance of many drugs including antiretroviral agents. Bacterial co-infections, low grade endotoxemia and immune activation are common in chronic HIV (+) patients. Inflammation due to endotoxin or HIV may influence the expression and activity of drug transporters in the kidney. The HIV-transgenic (HIV-Tg) rat develops immune dysfunction and AIDS associated conditions similar to humans. Thus, our objective was to study the effect of endotoxin on the renal expression of drug transporters in an HIV1-Tg rat model.
Methods: Five month male HIV1-Tg rats or wild-type (WT) littermates were treated with endotoxin (5 mg/Kg, i.p.) or saline (n=7/group). The mRNA expression of transporters and cytokines were measured 18 hours after treatment in kidney samples using qRT-PCR. Serum cytokine levels were measured by ELISA.
Results: As compared to WT, basal expression of IL-1β, IL-6, Oat2 and Urat1 was significantly higher in HIV-Tg rats while OCT1 levels were decreased. Endotoxin induced serum levels of inflammatory cytokines in both HIV1-Tg and WT, however interferon induction was significantly diminished in HIV-Tg. Endotoxin significantly down-regulated the expression of Mdra1, Oct3, Oat2, Urat1, Mate1 and Pept2 in both HIV-Tg and WT. Endotoxin significantly up-regulated the expression of Oct1 and Pept1 in HIV1-Tg but not WT. Levels of Mdr1b, Mrp4 and Octn2 were not changed.
Conclusion: Our results demonstrate that HIV and endotoxin- induced inflammation imposes alterations in the expression of many clinically important drug transporters in the kidney. Therefore, the renal clearance of drug substrates could be altered in patients with co-existing infections. This may provide new insight to potential drug-disease interactions.