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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 system back into the blood [4, 185]. Knockout of Oat3 results in the significantly increased accumulation of the antiviral drug oseltamivir [186], and dehydroepiandrosterone sulfate [187], while ex vivo studies of isolated choroid plexus from Oat3 knockout animals showed reduced accumulation of organic anions, including antivirals [4, 126]. Similarly, the placenta protects the fetus from exposure to toxic substrates and allows the delivery of pharmaceutical drugs (such as zidovudine prophylaxis against HIV) by similar mechanisms [188]. OAT4, for example, has been localized to the placenta and is known to transport many drugs such as zidovudine, antibiotics and anti‐hypertensives [189]. The discovery of the olfactory Oat, Oat6, also raises the possibility that SNPs in this gene could be important in determining the efficacy of nasally administered drugs [45, 190].

      4.5.6 Remote Sensing and Signaling Theory

Based on knockout metabolomics data and the growing amount of in vitro data indicating that Oats and other Slc and Abc transporters have reasonable or relatively high affinities for signaling molecules (e.g., odorants, cyclic nucleotides, prostaglandins), it has been postulated that they play a key role in the regulation of levels of signaling molecules in cellular, tissue, and body fluid compartments (Fig. 4.3) [45, 48, 51, 62]. This idea is further supported by the fact that not only is the expression of some of these transporters relatively tissue‐specific (e.g., OAT4 in placenta, Oat6 in olfactory mucosa) but also some Oats also have high selectivity for these types of signaling molecules: Oat2 for cGMP, Oat6 for odorants, OAT4 for sex steroid conjugates, Urat1 (originally Rst) for the antioxidant uric acid [45, 48, 51, 62].

These transporters are also clearly involved in the movement of other key metabolites and nutrients, including α‐ketoglutarate, vitamins, flavonoids, and gut microbiome products [120] across tissue barriers (“remote communication”). Moreover, they have been found to regulate central metabolic pathways directly or indirectly [37], and they

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