Renal and non-renal response of ABC and SLC transporters in chronic kidney disease

ABSTRACT

Introduction

The solute carrier (SLC) and the ATP-binding cassette (ABC) transporter superfamilies play essential roles in the disposition of small molecules (endogenous metabolites, uremic toxins, drugs) in the blood, kidney, liver, intestine, and other organs. In chronic kidney disease (CKD), the loss of renal function is associated with altered function of remote organs. As renal function declines, many molecules accumulate in the plasma. Many studies now support the view that ABC and SLC transporters as well as drug metabolizing enzymes (DMEs) in renal and non-renal tissues are directly or indirectly affected by the presence of various types of uremic toxins, including those derived from the gut microbiome; this can lead to aberrant inter-organ communication.

Areas covered

Here, the expression, localization and/or function of various SLC and ABC transporters as well as DMEs in the kidney and other organs are discussed in the context of CKD and systemic pathophysiology.

Expert opinion

According to the Remote Sensing and Signaling Theory (RSST), a transporter and DME-centric network that optimizes local and systemic metabolism maintains homeostasis in the steady state and resets homeostasis following perturbations due to renal dysfunction. The implications of this view for pharmacotherapy of CKD are also discussed.

KEYWORDS:

• Chronic Kidney Disease
• ATP Binding Cassette (ABC) Transporters
• solute Carrier (SLC) Transporters
• remote Sensing and Signaling Theory

Article highlights

• Chronic kidney disease (CKD) impacts the expression patterns of multi-specific, oligo-specific, and mono-specific transporters, as well as drug metabolizing enzymes (DMEs) in the kidney, liver, intestine, brain, and other tissues.

• Many of these altered ABC and SLC transporters as well as DMEs play critical roles in the movement of small molecule drugs, metabolites, signaling molecules, uric acid, and uremic toxins throughout the body. Therefore, it is important to consider potential drug-drug interactions, drug-metabolite interactions, and drug-uremic toxin interactions in CKD.

• Here we highlight studies, mainly in animal models of CKD, that support a key role for ABC and SLC transporters in remote communication between organs within the body (e.g. gut-liver-kidney axis) as well as between gut microbes and the host.

• In CKD, the myriad alterations in small molecule communication mediated by transporters and enzymes can be better understood in the context of the Remote Sensing and Signaling Theory (RSST). This theory aims to provide a conceptual framework that clarifies how ABC and SLC transporters as well as DMEs regulate inter-organ and inter-organismal (microbes-host) communication by metabolites, signaling molecules, and uremic toxins.

• The RSST may be particularly useful for understanding how ABC and SLC transporters as well as DMEs help restore homeostasis after perturbation of organ function such as occurs in CKD.

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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 partly funded by the Nancy Kaehr Chair in Research.