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Advanced oxidation protein products upregulate ABCB1 expression and activity via HDAC2-Foxo3α-mediated signaling in
Tianrong Xun1, Zhufen Lin1, Mimi Zhang1
1Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
Abstract:
The unpredictable pharmacokinetics of non-renal cleared drugs in chronic kidney disease (CKD) patients is associated with the activity of drug transporters. However, the mechanisms underlying regulation of drug transporters are yet to be established. In this study, we demonstrated the involvement of a HDAC2-Foxo3α pathway in advanced oxidation protein products (AOPPs)-induced ATP-binding cassette subfamily B member 1 (ABCB1) expression and activity. The correlation of AOPPs accumulation with concentration of cyclosporine in plasma was evaluated in 194 patients with transplantation. Molecular changes in acetylation of various histones and related regulatory molecules were examined in HepG2 cell cultures treated with AOPPs. Accumulation of AOPPs in serum in relation to molecular changes in HDAC2-Foxo3α in vivo were evaluated in 5/6 nephrectomy (5/6 nx) and oral adenine (Adenine) CKD rat models. Interestingly, the cyclosporine level was negatively correlated with AOPPs in plasma. In addition, AOPPs markedly suppressed the expression of histone deacetylase 2 (HDAC2), inducing ABCB1 expression and activity in vitro and in vivo. Importantly, AOPPs modulated phosphorylation of Foxo3α and the upstream Akt protein. Our findings indicate that AOPPs regulate the expression and activity of ABCB1 via reducing HDAC2 expression and activating Foxo3α-dependent signaling. The collective results support the utility of AOPPs as a potential target for drug and/or dosage adjustment in CKD patients. Targeting of AOPPs presents a novel approach to regulate non-renal clearance.
Insights
Advanced oxidation protein products (AOPPs) impact drug clearance in chronic kidney disease (CKD). This study reveals AOPPs regulate ABCB1 transporter activity via a HDAC2-Foxo3α pathway, offering a new therapeutic target for CKD patients.
Area of Science:
- Pharmacology and Toxicology
- Nephrology
- Molecular Biology
Background:
- Drug pharmacokinetics are unpredictable in chronic kidney disease (CKD) due to altered drug transporter activity.
- Mechanisms regulating drug transporters in CKD remain poorly understood, impacting drug efficacy and safety.
Purpose of the Study:
- To elucidate the regulatory pathway of ATP-binding cassette subfamily B member 1 (ABCB1) expression and activity induced by advanced oxidation protein products (AOPPs).
- To investigate the role of the HDAC2-Foxo3α pathway in AOPPs-mediated ABCB1 regulation in CKD.
Main Methods:
- Correlation analysis of AOPPs and cyclosporine levels in 194 CKD transplant patients.
- In vitro studies using HepG2 cells treated with AOPPs to examine molecular and histone acetylation changes.
- In vivo evaluation in 5/6 nephrectomy and adenine-induced CKD rat models to assess AOPPs, HDAC2, and Foxo3α.
- Analysis of Akt protein phosphorylation.
Main Results:
- AOPPs accumulation was negatively correlated with plasma cyclosporine levels.
- AOPPs suppressed histone deacetylase 2 (HDAC2) expression, leading to increased ABCB1 expression and activity in vitro and in vivo.
- AOPPs modulated the phosphorylation of Foxo3α and its upstream regulator, Akt.
Conclusions:
- AOPPs regulate ABCB1 expression and activity by reducing HDAC2 and activating Foxo3α signaling.
- AOPPs represent a potential therapeutic target for managing drug clearance and dosage adjustments in CKD patients.
- Targeting AOPPs offers a novel strategy to modulate non-renal drug clearance in CKD.
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