Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling

Abstract

BackgroundIn the setting of chronic kidney disease (CKD), altered extra-renal urate handling may be necessary to regulate plasma uric acid. The Remote Sensing and Signaling Hypothesis (Nigam S. What do drug transporters really do? Nat Rev Drug Discov 2015; 14: 29–44) suggests that multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters in different tissues are part of an inter-organ communication system that maintains levels of urate and other metabolites after organ injury.MethodsData from the Chronic Renal Insufficiency Cohort (CRIC; n = 3598) were used to study associations between serum uric acid and single nucleotide polymorphisms (SNPs) on the following uric acid transporters: ABCG2 (BRCP), SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A10 (OAT5), SLC22A11 (OAT4), SLC22A12 (URAT1), SLC22A13 (OAT10), SLC17A1-A3 (NPTs), SLC2A9 (GLUT9), ABCC2 (MRP2) and ABCC4 (MRP4). Regression models, controlling for principal components age, gender and renal function, were run separately for those of European (EA) and African ancestry (AA), and P-values corrected for multiple comparisons. A twin cohort with participants of EA and normal renal function was used for comparison.ResultsAmong those of EA in CRIC, statistically significant signals were observed for SNPs in ABCG2 (rs4148157; beta-coefficient = 0.68; P = 4.78E-13) and SNPs in SLC2A9 (rs13125646; beta-coefficient = −0.30; P = 1.06E-5). Among those of AA, the strongest (but not statistically significant) signals were observed for SNPs in SLC2A9, followed by SNPs in ABCG2. In the twin study (normal renal function), only SNPs in SLC2A9 were significant (rs4481233; beta-coefficient=−0.45; P = 7.0E-6). In CRIC, weaker associations were also found for SLC17A3 (NPT4) and gender-specific associations found for SLC22A8 (OAT3), SLC22A11 (OAT4), and ABCC4 (MRP4).ConclusionsIn patients of EA with CKD (CRIC cohort), we found striking associations between uric acid and SNPs on ABCG2, a key transporter of uric acid by intestine. Compared with ABCG2, SLC2A9 played a much less significant role in this subset of patients with CKD. SNPs in other SLC (e.g. SLC22A8 or OAT3) and ABC (e.g. ABCC4 or MRP4) genes appear to make a weak gender-dependent contribution to uric acid homeostasis in CKD. As renal urate transport is affected in the setting of declining kidney function, extra-renal ABCG2 appears to play a compensatory role—a notion consistent with animal studies and the Remote Sensing and Signaling Hypothesis. Overall, the data indicate how different urate transporters become more or less important depending on renal function, ethnicity and gender. Therapies focused on enhancing ABCG2 urate handling may be helpful in the setting of CKD and hyperuricemia.

The systems biology of uric acid transporters

“…In the setting of renal disease, intestinal excretion of urate appears to become important for maintaining uric acid levels, suggesting some sort of mechanism for remote communication between the failing kidney and intestine with respect to uric acid homeostasis (Fig. 2) [15,25]. …”

“…In keeping with the idea of remote communication (remote sensing and signaling) between organs in the setting of injury (possibly via substrates transported by transporters in distinct organs), the role of intestinal excretion of uric acid may be essential in the setting of renal failure. Consistent with this view, human single nucleotide polymorphisms (SNPs) in ABCG2 become more important in the setting of renal disease [15]. …”

“…In whites and African–Americans with renal disease and hyperuricemia, URAT1 is one of the few genes discussed in this review that do not appear to significantly contribute to the hyperuricemia. Although there is no doubt about the role of URAT1 in renal urate handling, SNPs in URAT1 may be more important in certain Asian populations than in whites and African–Americans [15]. This highlights the need, in future studies, to understand the key genes regulating uric acid levels in different ethnicities.…”

“…In GWAS studies, however, these OATs (and others such as OAT4 and OAT10), although implicated, do not nearly achieve the levels of significance seen for genes like SLC2A9 and ABCG2 [15]. …”

“…These substances also accumulate within cells and may be directly cytotoxic to cells, including those of the proximal tubule of the kidney which are the main cells involved in urate elimination from the plasma to the urine [6]. Until recently, the bulk of attention regarding uric acid homeostasis has been on the role of renal uric acid transporters, but there is growing attention with regards to intestinal transporters, particularly in the setting of renal dysfunction [6,15,16]. Many of these are multispecific SLC and ABC ‘drug’ transporters as well as their close relatives that have more limited substrate selectivities [11,17,18].…”