α-Ketoglutarate-related inhibitors of HIF prolyl hydroxylases are substrates of renal organic anion transporters 1 (OAT1) and 4 (OAT4)
α-Ketoglutarate-related inhibitors of HIF prolyl hydroxylases are substrates of renal organic anion transporters 1 (OAT1) and 4 (OAT4)
复制标题
DOI：
10.1007/s00424-012-1140-9
复制
发表时间：
2012-10-01
影响因子：
4.5
通讯作者：
Burckhardt, Birgitta C.
中科院分区：
文献类型：
--
作者：
Hagos, Yohannes;Schley, Gunnar;Burckhardt, Birgitta C.
2-氧戊二酸或α -酮戊二酸（α KG）是HIF脯氨酰羟化酶1-3的底物，在氧气存在下降低细胞缺氧诱导因子1 α (HIF-1 α)的水平。即使在氧气存在的情况下，α KG类似物也可用于稳定HIF-1 α，从而为治疗肾脏疾病提供了一种新的治疗选择。在肾脏中，有机阴离子转运体1和3（分别为OAT1和OAT3）与钠依赖性二羧酸转运体3 （NaDC3）和OAT4合作，可能负责α KG类似物的摄取进入和流出肾小管细胞。利用放射性标记的底物对氨基马嘌呤酸酯（PAH, OAT1）、雌性酮-3-硫酸酯（ES; OAT3, OAT4）和琥珀酸酯（NaDC3），对n -草酰甘氨酸（NOG）、二甲基氧基甘氨酸（DMOG）、2,4-二乙基吡啶二羧酸酯（2,4- dpd）和吡啶-2,4-二羧酸（PDCA）进行顺式抑制和反式刺激实验。这些α - KG类似物均不与NaDC3相互作用。2,4- dpd和PDCA适度抑制OAT3对ES的摄取。NOG、2,4- dpd和PDCA能显著抑制OAT1对PAH的摄取，但DMOG不能。反式刺激实验和证明HIF-1 α稳定的实验表明NOG和PDCA，而不是2,4- dpd，被OAT1易位。所有化合物都刺激了OAT4对ES的摄取，但只有PDCA稳定了HIF-1 α。数据表明，OAT1参与近端小管细胞基底外膜对NOG和PDCA的摄取，而OAT4可能将这些化合物释放到初尿中。
2-Oxoglutarate or alpha-ketoglutarate (alpha KG) is a substrate of HIF prolyl hydroxylases 1-3 that decrease cellular levels of the hypoxia-inducible factor 1 alpha (HIF-1 alpha) in the presence of oxygen. alpha KG analogs are applied to stabilize HIF-1 alpha even in the presence of oxygen and thus provide a novel therapeutic option in treating kidney diseases. In the kidneys, the organic anion transporters 1 and 3 (OAT1 and OAT3, respectively) in cooperation with the sodium-dependent dicarboxylate transporter 3 (NaDC3) and the OAT4 might be responsible for the uptake of alpha KG analogs into and the efflux out of the tubular cells. Using the radiolabelled substrates p-aminohippurate (PAH, OAT1), estrone-3-sulfate (ES; OAT3, OAT4), and succinate (NaDC3), N-oxalylglycine (NOG), dimethyloxalyl glycine (DMOG), 2,4-diethylpyridine dicarboxylate (2,4-DPD), and pyridine-2,4-dicarboxylic acid (PDCA) were tested in cis-inhibition and trans-stimulation experiments. None of these alpha KG analogs interacted with NaDC3. 2,4-DPD and PDCA inhibited ES uptake by OAT3 moderately. NOG, 2,4-DPD and PDCA, but not DMOG, inhibited PAH uptake by OAT1 significantly. trans-Stimulation experiments and experiments demonstrating stabilization of HIF-1 alpha revealed that NOG and PDCA, but not 2,4-DPD, are translocated by OAT1. All compounds trans-stimulated ES uptake by OAT4, but only PDCA stabilized HIF-1 alpha. The data suggest that OAT1 is involved in the uptake of NOG and PDCA across the basolateral membrane of proximal tubule cells, whereas OAT4 may release these compounds into the primary urine.