Endotoxin Modulates the Expression of Renal Drug Transporters in HIV-1 Transgenic Rats

Abstract

PURPUSE: Bacterial co-infections and low grade endotoxemia are common in HIV patients. Inflammation due to endotoxin or HIV may influence the expression and activity of transporters. Kidney transporters influence renal drug clearances including many antiretroviral agents. Our objective was to study the effect of endotoxin and HIV on the renal expression of drug transporters in an HIV-transgenic (HIV-Tg) rat model. These rats develop immune dysfunction and AIDS-associated conditions like humans. METHODS: Endotoxin or saline was administered intraperitoneally to HIV-Tg or wild type (WT) littermates and kidneys were collected 18 hours later. Expression of transporters and cytokines were measured by qRT-PCR and Western blots. Serum cytokine levels were measured by ELISA. RESULTS: Endotoxin induced serum levels of IL-6, TNF-α and IFN-γ in both HIV-Tg and WT animals. The basal mRNA expression of Oct2, Oct3, Octn1, Mate1, Urat1 and Ent1was significantly lower (33-60%) and the expression of Ent2 and Pept2 was significantly higher (33-45%) in HIV-Tg as compared to WT. While endotoxin significantly downregulated the mRNA expression of Mdra1 and Pept2 in both HIV and WT groups (69-78%), it imposed a significant reduction on the mRNA expression of Oct2, Oct3, Octn1, Mate1, Oat2, urat1, and Ent1 (54-83%) only in the WT group. Endotoxin significantly increased the mRNA expression of Pept1 (140%) in both WT and HIV groups. CONCLUSIONS: HIV and endotoxin each imposed alterations in the expression of many clinically important renal drug transporters although co-infection did not augment this effect. Viral and/or bacterial infections may impact the renal clearance of drug substrates in patients and could potentially be a source of drug-disease interactions.

Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats

“…Therefore, the implications of decreased transcript levels are not clear. An endotoxin-mediated downregulation in the renal mRNA and protein expression of ENT1 has been previously reported in transgenic-HIV male rats [60]. We previously found that poly I:C imposed an increase rather than a decrease in the renal mRNA expression of Ent1 in pregnant rats at term [16].…”

“…Therefore, the implications of these findings are not clear. Endotoxin exposure has also been found to decrease transcript levels of Pept2 in the kidneys of male rats and mice [60].…”

Thioacetamide-Induced Acute Liver Injury Increases Metformin Plasma Exposure by Downregulating Renal OCT2 and MATE1 Expression and Function

“…Similarly, Schmidt-Lauber et al reported that the cytokines TNF-α, IL-6, and IL-1β decreased the expression of MATE1 mRNA and protein in MATE1-transfected HEK-293 cells [26]. The mRNA expression of OCT2 and MATE1 was found to be decreased in endotoxin-infected mice, which were characterized by elevated serum levels of IL-6, TNF-α, and IFN-γ [27]. In a rat model of hyperuricemia, the mRNA levels of MATE1 and OCT2 were decreased, leading to an increased accumulation of metformin in kidney tissue [28].…”

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

“…It is noteworthy that different viral infections bring different changes of the renal transporter levels. The poly I:C infected pregnant rat showed lowered levels of OAT1/3, OATP4C1, BCRP, and MRP2 ( Karimian Pour and Piquette-Miller, 2020 ), but the HIV-1 transgenic rat showed reduced OCT2 and MATE1 levels ( Karimian Pour and Piquette-Miller, 2018 ). A hepatitis B virus infection could also damage kidneys, and it could downregulate some kidney transporters ( Zuo et al, 2020 ).…”