Читать книгу Drug Transporters - Группа авторов - Страница 133

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].