Vallon Volker, Eraly Satish A, Wikoff William R, Rieg Timo, Kaler Gregory, Truong David M, Ahn Sun-Young, Mahapatra Nitish R, Mahata Sushil K, Gangoiti Jon A, Wu Wei, Barshop Bruce A, Siuzdak Gary, Nigam Sanjay K
Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego and VASDHCS, 3350 La Jolla Village Drive (9151), San Diego, CA 92161, USA.
J Am Soc Nephrol. 2008 Sep;19(9):1732-40. doi: 10.1681/ASN.2008020180. Epub 2008 May 28.
Renal organic anion transporters (OAT) are known to mediate the excretion of many drugs, but their function in normal physiology is not well understood. In this study, mice lacking organic anion transporter 3 (Oat3) had a 10 to 15% lower BP than wild-type mice, raising the possibility that Oat3 transports an endogenous regulator of BP. The aldosterone response to a low-salt diet was blunted in Oat3-null mice, but baseline aldosterone concentration was higher in these mice, suggesting that aldosterone dysregulation does not fully explain the lower BP in the basal state; therefore, both targeted and global metabolomic analyses of plasma and urine were performed, and several potential endogenous substrates of Oat3 were found to accumulate in the plasma of Oat3-null mice. One of these substrates, thymidine, was transported by Oat3 expressed in vitro. In vivo, thymidine, as well as two of the most potent Oat3 inhibitors that were characterized, reduced BP by 10 to 15%; therefore, Oat3 seems to regulate BP, and Oat3 inhibitors might be therapeutically useful antihypertensive agents. Moreover, polymorphisms in human OAT3 might contribute to the genetic variation in susceptibility to hypertension.
已知肾脏有机阴离子转运体（OAT）介导多种药物的排泄，但其在正常生理功能中的作用尚不清楚。在本研究中，缺乏有机阴离子转运体3（Oat3）的小鼠血压比野生型小鼠低10%至15%，这增加了Oat3转运一种内源性血压调节因子的可能性。Oat3基因敲除小鼠对低盐饮食的醛固酮反应减弱，但这些小鼠的基线醛固酮浓度较高，这表明醛固酮失调并不能完全解释基础状态下的低血压；因此，对血浆和尿液进行了靶向和全局代谢组学分析，发现几种潜在的Oat3内源性底物在Oat3基因敲除小鼠的血浆中积累。其中一种底物胸苷可被体外表达的Oat3转运。在体内，胸苷以及两种已被鉴定的最有效的Oat3抑制剂可使血压降低10%至15%；因此，Oat3似乎调节血压，Oat3抑制剂可能是有治疗作用的抗高血压药物。此外，人类OAT3基因的多态性可能导致高血压易感性的遗传变异。
