Examination of the emerging role of transporters in the assessment of nephrotoxicity

ABSTRACT

Introduction

The kidney is vulnerable to various injuries based on its function in the elimination of many xenobiotics, endogenous substances and metabolites. Since transporters are critical for the renal elimination of those substances, it is urgent to understand the emerging role of transporters in nephrotoxicity.

Areas covered

This review summarizes the contribution of major renal transporters to nephrotoxicity induced by some drugs or toxins; addresses the role of transporter-mediated endogenous metabolic disturbances in nephrotoxicity; and discusses the advantages and disadvantages of in vitro models based on transporter expression and function.

Expert opinion

Due to the crucial role of transporters in the renal disposition of xenobiotics and endogenous substances, it is necessary to further elucidate their renal transport mechanisms and pay more attention to the underlying relationship between the transport of endogenous substances and nephrotoxicity. Considering the species differences in the expression and function of transporters, and the low expression of transporters in general cell models, in vitro humanized models, such as humanized 3D organoids, shows significant promise in nephrotoxicity prediction and mechanism study.

KEYWORDS:

• Transporters
• nephrotoxicity
• xenobiotics
• endogenous metabolism
• models

Article highlights

• Transporter-mediated transfer of xenobiotics is essential in renal elimination, which probably leads to renal accumulation and ultimately results in nephrotoxicity.

• The expression or activity of transporters is altered during drug treatments or under pathological states, which accounts for drug-drug interactions (DDIs) or unexpected nephrotoxicity.

• Transporters mediate the tubular disposition of endogenous substrates, such as glucose and fatty acid. Alterations of transporters by disease states or drug treatments interfere with the endogenous metabolism, which may further contribute to nephrotoxicity.

• Since compatible expression and function of transporters are crucial for nephrotoxicity studies in tubular cells, in vitro models based on renal transporters can provide useful tools for the prediction and assessment of nephrotoxicity.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Natural Science Foundation of China (82073927, 81872929).