As described above, one disease thought to be a result of altered organic anion clearance is gout, which is associated with uric acid crystal deposition in the kidney (resulting in nephropathy) or within joints (resulting in an acutely painful inflammatory arthritis) caused by hyperuricemia [159]. The organic anion transporter URAT1 (SLC22A12), the human homolog of the gene first identified as Rst, is thought to transport uric acid across the apical proximal tubular cell membrane from the tubule lumen back into the cell [23, 24]. Accordingly, case‐control and cohort studies have suggested that loss of function polymorphisms on SLC22A12 are associated with hypouricemia, due to inefficient tubular reabsorption of uric acid [160]. Nevertheless, the molecular basis of renal urate handling in vivo remains poorly understood, with at least 10 genes, mostly transporters, suggested to be associated with hyperuricemia [160]. In addition, analysis of the Rst knockout animal found that multiple transporters, including Rst, Oat1, Oat3, and others, contribute to overall urate handling perhaps as a larger transporter network [51, 122, 161]. Finally, mutations in SLC22A12 have also been linked to hypouricemic hyperuricosuria, which can lead to exercise‐induced uric acid stones [162]. Interestingly, as renal function declines and transport by OATs and URAT1 is compromised, it seems that intestinal ABCG2 is upregulated to serve as another route for urate transport [163].
Acute kidney injury (AKI) is a common and complex condition, especially for patients in intensive care units. Drug/toxicant‐induced renal toxicity and renal ischemia/reperfusion are the well‐recognized causes of AKI [46]. Renal ischemia/reperfusion often reduces glomerular filtration rate (GFR) and impairs tubular functions, such as secretion and reabsorption [164, 165]. In the kidneys of the ischemic rats, the expression levels of Oat1 and Oat3 mRNA and protein were both decreased [164, 166]. Anti‐inflammatory drugs meclofenamate, quercetin, and resveratrol reduced indoxyl sulfate accumulation during AKI and ameliorated the reduction of Oat1 and Oat3 protein expression in ischemic AKI rats [167, 168]. Prostaglandin E2, through E‐type prostanoid receptor type 4, decreased the mRNA levels of Oat1 and Oat3 in rats with ischemic‐induced AKI [169, 170]. A variety of clinical therapeutics including aminoglycosides antibiotics and angiotensin‐converting‐enzyme inhibitors can give rise to renal toxicity and induce AKI [171]. Previous research revealed that gentamicin can cause necrosis of proximal tubule cells, which would inhibit protein synthesis in kidney and induce AKI. Furthermore, gentamicin was able to increase the levels of superoxide anion and hydrogen peroxide in renal cortical cells, which would also contribute to renal toxicity [172]. In a rat model of gentamicin‐induced AKI, the levels of both plasma creatinine and blood urea nitrogen were increased, indicating reduced renal function and toxicity. In this AKI model, both the mRNA and protein expressions of Oat1 and Oat3 were significantly decreased. It was suggested that gentamicin‐caused toxicity down‐regulated kidney Oat1 and Oat3 expression, which contributed to the reduced renal function and accumulated endogenous substances [173]. Resveratrol, an anti‐inflammatory and antioxidant agent, reduced methotrexate‐induced renal toxicity in rats via decreasing Oat‐mediated kidney elimination of methotrexate. This reduced toxicity was mainly due to direct inhibition by resveratrol on Oat1 and Oat3 [174].
Clinical observations between kidney diseases and renal OATs are often complex and intertwined. On one hand, kidney injury and diseases could directly affect renal OAT expression, function, and localization. On the other hand, direct damage on proximal tubule cells and OATs could also change various renal functions, leading to kidney disease progression. Animal and clinical studies have revealed possible correlations between them [46, 85, 152, 154,175–177].
4.5.5 Clinical Pharmacology
Because the OATs are found at crucial cellular interfaces for various excretory organs (such as the liver and kidneys), variations or polymorphisms in these genes have been hypothesized to cause clinically important differences in drug efficacy and handling of commonly prescribed pharmaceuticals (e.g., ACE inhibitors, methotrexate, and NSAIDs). In particular, there has been considerable interest in single‐nucleotide polymorphisms (SNPs) in this family of genes and their potential role in drug handling by the kidney, thereby affecting drug concentrations and half‐lives in the serum. Initial studies of a limited set of human polymorphisms in OATs indicated that coding region polymorphisms in OAT1 (SLC22A6) and OAT3 (SLC22A8) are not common, perhaps due to the previously described role in endogenous metabolism [4]. In contrast, SNPs in the noncoding regions of these genes are comparatively more frequent and have the potential to regulate the expression of the transporters [4, 178]. The impact of SNPs in OATs has mostly been studied in the context of drugs. Through a combination of in vitro experiments and GWAS, it has been shown that certain SNPs in SLC22A6 can impact its ability to interact with antivirals, SNPs in SLC22A8 influence cefotaxime clearance, SNPs in SLC22A11 diminish torsemide clearance, SNPs in SLC22A9 impact hepatic uptake of pravastatin, and SNPs in SLC22A12 have been shown to affect its activity [179].
Differences in the expression of OATs may significantly alter the elimination of many pharmaceutical agents, thereby increasing the risk of a significant adverse drug reaction [76]. It has also been suggested that, to understand the overall impact of human SNPs on drug transport across epithelial tissues, combinations of SNPs in both apical and basolateral drug transporters in the organic anion transport pathway may be particularly important [4]. Since the apical step may be partly or largely mediated by ABC transporters, this would imply that, to understand renal drug excretion in the context of SNPs, one might at the very least consider OAT1, OAT3, MRP2 and MRP4, among others.
However, genomic variation (either at the level of expression or function) may be exacerbated (change in drug efficacy or toxicity) in certain disease states (an environmental‐gene interaction). For example, expression of OAT3 is thought to be directly related to the clearance of cefazolin, a commonly prescribed antibiotic. This relationship, however, was only observed in patients with mesangial proliferative glomerulonephritis whereby decreased expression of SLC22A8 mRNA was strongly associated with decreased renal clearance of cefozolin [180]. This implies that certain patients are at a higher risk of developing cefazolin‐related drug toxicity (e.g., hepatitis) depending on individual differences in expression of the SLC22A8 gene. In addition, a study investigating the effects of drug metabolizing enzyme and transporter gene variation on treatment for acute myeloid leukemia patients found that response to the chemotherapy agent, gemtuzumab ozogamicin, was dependent on SLC22A12 genotype [181]. Therefore, genomic variation may be especially important in stressed or disease‐specific environments. Altered handling of antibiotics and diuretics has been associated with polymorphisms in coding or noncoding regions of OATs [178]. Mercury toxicity has also been associated with SNPs in SLC22A6 and SLC22A8 [182].
A study in humans including normal subjects and patients with CKD provided evidence that patients with CKD had a higher frequency of the −475 SNP in the 5′ regulatory region in SLC22A6 than normal subjects. Furthermore, the −475 SNP in SLC22A6 with T to G transversion reduced the binding of hepatoma‐derived growth factor (HDGF). HDGF is a known transcription repressor and can suppress OAT1 protein expression, suggesting an increase of OAT1 expression and renal uptake of toxins, and nephrotoxicity with the −475 SNP [183]. Cho et al. analyzed subjects with normal uric acid level and subjects with hyperuricemia [184] and found that five new SNPs in the human SLC22A12 gene were significantly associated with uric acid concentration in blood. Among the five SNPs, rs75786299 had the highest association with hyperuricemia, followed by rs7929627 and rs3825017, while rs11602903 and rs121907892 were negatively correlated with hyperuricemia. One study found that a SNP (rs3793961) in SLC22A8 had an association with lower serum uric acid levels among men with CKD [163].
There is also a growing body of research that is delineating the importance of OATs in organ systems other than the kidney, and these are only briefly mentioned here. For example, Oat3 is expressed in both the blood–brain barrier and in the blood‐cerebral spinal fluid barrier where it is believed to act as an efflux transporter mediating the movement of organic anion from the central nervous
