Taurodeoxycholic acid impairs the function and expression of organic anion transporter 2 through farnesoid X receptor activation during acute kidney injury to chronic kidney injury transition

Abstract

Acute kidney injury (AKI) is a worldwide health issue with risk of progressing to chronic kidney disease (CKD). The kidney harbors various transporters that may be involved in certain disease processes, in addition to mediating drug transport. Kidney injury may compromise the effectiveness and safety of medications by disturbing functions of these transporters. However, so far, there is a poor understanding of the changes in transporters and their mechanisms during AKI-to-CKD transition. In the present study, the expression of organic anion transporter 2 (OAT2) was found to be gradually decreased through bioinformatics analysis during AKI-to-CKD transition. Subsequent experiments via quantitative reverse-transcription polymerase chain reaction and western blot validated gradual reduction of OAT2 mRNA and protein levels during AKI-to-CKD transition. Pharmacokinetic studies revealed that OAT2 downregulation during AKI-to-CKD transition led to increased plasma exposure of its substrate, acyclovir. Metabolomics identified a gradual increase in taurodeoxycholic acid (TDCA) levels during AKI-to-CKD transition. Further in vitro experiments demonstrated that TDCA activated the farnesoid X receptor (FXR) in a concentration-dependent manner, leading to suppressed OAT2 expression. Both in vivo and in vitro experiments indicated that downregulated OAT2 expression induced by TDCA could be reversed by FXR inhibitor (guggulsterone) or by knocking down FXR. In conclusion, a gradual increase in TDCA levels plays a pivotal role in mediating FXR activation, which consequently disrupts the expression and function of renal OAT2 during AKI-to-CKD transition, resulting in increased drug plasma exposure. These findings emphasize the importance of precision medicine for AKI-to-CKD patients using OAT2 substrate drugs, providing a robust theoretical foundation for rational medications and treatment strategies tailored to special populations. SIGNIFICANCE STATEMENT: This study for the first time identified a gradual decrease in organic anion transporter 2 expression during acute kidney injury-to- chronic kidney disease transition, leading to increased plasma exposure of acyclovir. There existed increased taurodeoxycholic acid levels during acute kidney injury to chronic kidney disease transition, which could inhibit organic anion transporter 2 expression by activating the farnesoid X receptor.

Keywords: Acute kidney injury to chronic kidney disease transition; Farnesoid X receptor; Organic anion transporter 2; Pharmacokinetics; Taurodeoxycholic acid.