Development of in vivo evaluation system of human organic anion transpoter

在慢性肾脏病(CKD)患者中，尿毒症毒素的积聚导致血压难以控制，损害肾功能，恶化预后。减少累积的尿毒症毒素可以防止高血压的发展和持续的肾脏损害，但到目前为止还没有确定的治疗方法。我们已经证明，人肾特异的有机阴离子转运体SLCO4C1在大鼠肾脏中的过表达可以减少高血压、心脏增大和肾衰竭时的炎症，并减少血浆尿毒症毒素、琥珀酸胍(GSA)、不对称二甲基精氨酸(ADMA)和反式乌头酸酯。反式乌头酸酯是一种新发现的尿毒症毒素，通过转录分析，我们发现他汀类药物上调了SLCO4C1的转录。他汀类药物增强肾脏近端功能，促进尿毒症毒素的排泄，从而预防肾衰竭时的高血压和肾脏炎症。这些数据表明，SLCO4C1上调为CKD患者提供了一种新的基于转运体的治疗策略，以减少肾脏损害和危及生命的事件。

In chronic kidney disease (CKD) patients, the accumulation of uremic toxins causes difficulty in controlling blood pressure, impairs renal function and worsens prognosis. The reduction of accumulated uremic toxins protects against the development of hypertension and ongoing renal damage, but there is no established treatment so far. We have demonstrated that the overexpression of human kidney-specific organic anion transporter SLCO4C1 in rat kidney reduced hypertension, cardiomegaly and inflammation in renal failure together with a reduction of plasma uremic toxins, guanidinosuccinate (GSA), asymmetric dimethylarginine (ADMA) and trans-aconitate. Trans-aconitate is a newly identified uremic toxin.By transcriptional analysis, we found that the SLCO4C1 transcription is upregulated by various statins. Statins potentate renal proximal function and facilitate excretion of uremic toxins, resulting preventing hypertension and renal inflammation in the renal failure. These data suggest that SLCO4C1 upregulation provides a novel transporter-based therapeutic strategy for CKD patients to reduce renal damage and life-threatening events.