Identification of ABCG2 as an Exporter of Uremic Toxin Indoxyl Sulfate in Mice and as a Crucial Factor Influencing CKD Progression

Abstract

Chronic kidney disease (CKD) patients accumulate uremic toxins in the body, potentially require dialysis, and can eventually develop cardiovascular disease. CKD incidence has increased worldwide, and preventing CKD progression is one of the most important goals in clinical treatment. In this study, we conducted a series of in vitro and in vivo experiments and employed a metabolomics approach to investigate CKD. Our results demonstrated that ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a major transporter of the uremic toxin indoxyl sulfate. ABCG2 regulates the pathophysiological excretion of indoxyl sulfate and strongly affects CKD survival rates. Our study is the first to report ABCG2 as a physiological exporter of indoxyl sulfate and identify ABCG2 as a crucial factor influencing CKD progression, consistent with the observed association between ABCG2 function and age of dialysis onset in humans. The above findings provided valuable knowledge on the complex regulatory mechanisms that regulate the transport of uremic toxins in our body and serve as a basis for preventive and individualized treatment of CKD.

Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease

“…Kynurenic acid, which has a role in signaling in the central nervous system, is also an AHR ligand, as well as a ligand of the G protein-coupled receptor 35 (GPR35), which has also been associated with a number of diseases, including hypertension and heart failure (71,72). In this regard, it is worth noting that the metabolic derangements of uremia reflect aberrant functioning of normal interorgan and interorganismal remote sensing and signaling, involving, among other ADME genes, multispecific transporters, such as the OATs (31,(73)(74)(75)(76)(77).…”

Dysfunctional ABCG2 gene polymorphisms are associated with serum uric acid levels and all-cause mortality in hemodialysis patients

“…There are several possible mechanisms for the association between ABCG2 polymorphism and mortality. First, the ABCG2 transporter regulates not only uric acid, but also uremic toxins in chronic kidney disease (CKD) [12]. Our recent study showed that ABCG2-knockout CKD mice had higher mortality and decreased indoxyl sulfate excretion in the kidney and intestine [12].…”

“…First, the ABCG2 transporter regulates not only uric acid, but also uremic toxins in chronic kidney disease (CKD) [12]. Our recent study showed that ABCG2-knockout CKD mice had higher mortality and decreased indoxyl sulfate excretion in the kidney and intestine [12]. Indoxyl sulfate is a protein-bound uremic toxin resulting from bacterial metabolism of dietary tryptophan and is reported to be associated with mortality in CKD and dialysis patients [35−37].…”

“…Fifth, serum indoxyl sulfate levels were not measured. Because a previous study reported that ABCG2 gene type is associated with sulfate levels [12], a future study is needed to investigate the association between ABCG2 gene type and sulfate levels in patients with CKD.…”

“…We recently found that ABCG2 is a major transporter of the uremic toxin indoxyl sulfate [12]. ABCG2-knockout 1 3 mice had lower survival rates and higher plasma indoxyl sulfate levels during kidney dysfunction [12]. In addition, several studies have also reported that ABCG2 plays an important role in stimulating inflammation and regulating autophagy [13−15].…”