Shim Won-Sik, Park Joo-Hyun, Ahn Sun-Joo, Han Liwei, Jin Qing-Ri, Li Hong, Choi Min-Koo, Kim Dae-Duk, Chung Suk-Jae, Shim Chang-Koo
National Research Laboratory of Transporters, Targeted New Drug Design and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
J Pharm Sci. 2009 Feb;98(2):739-47. doi: 10.1002/jps.21442.
Although acute renal failure (ARF) has been an area of extensive research in recent decades, our understanding of ARF is far from complete. Organic cations (OCs) are primarily excreted via vectorial transport by various renal organic cation transporters (OCTs). It is reasonable to assume that ARF may alter the expression profiles of these transporters. In a rat ARF model, induction of ARF by uranyl nitrate (UN) treatment significantly decreased the levels of Oct2 (slc22a2) mRNA and protein in the kidney medulla. mRNA expression of the other OCTs was not appreciably altered. The plasma level of testosterone, a well-known regulator of Oct2, was not changed, suggesting that the Oct2 down-regulation is testosterone-independent. The effect of reduced Oct2 expression on the distribution of a model OC, tetraethylammonium (TEA), in various rat tissues including kidney cortex and kidney medulla was investigated during steady state plasma TEA concentrations. The steady state tissue-to-plasma (T/P) TEA ratio was decreased in the kidney medulla (approximately 15-fold) during ARF. These results indicate that, in a rat model of ARF, reduced Oct2 expression in the kidney medulla results in decreased distribution of TEA to the kidney medulla, thereby reducing renal clearance of TEA in UN-ARF rats.
尽管近几十年来急性肾衰竭（ARF）一直是广泛研究的领域，但我们对ARF的了解仍远未完善。有机阳离子（OCs）主要通过各种肾有机阳离子转运体（OCTs）的向量转运进行排泄。可以合理推测，ARF可能会改变这些转运体的表达谱。在大鼠ARF模型中，用硝酸铀酰（UN）处理诱导ARF可显著降低肾髓质中Oct2（slc22a2）mRNA和蛋白的水平。其他OCTs的mRNA表达没有明显改变。睾酮是Oct2的著名调节剂，其血浆水平未发生变化，这表明Oct2的下调与睾酮无关。在稳态血浆四乙铵（TEA）浓度期间，研究了Oct2表达降低对模型OC（四乙铵，TEA）在包括肾皮质和肾髓质在内的各种大鼠组织中分布的影响。在ARF期间，肾髓质中的稳态组织与血浆（T/P）TEA比值降低（约15倍）。这些结果表明，在大鼠ARF模型中，肾髓质中Oct2表达降低导致TEA在肾髓质中的分布减少，从而降低了UN-ARF大鼠中TEA的肾清除率。
