Yong-Wen Jin, Yan-Rong Ma, Yu-Ting Liu, Yang Jin-Ru, Ming-Kang Zhang, Ran Feng-Lin, Yang Chen, Xin-An Wu
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引用次数: 0
摘要
早期识别药物诱发的急性肾损伤(AKI)对于预防肾损伤至关重要。肾小管通常是最先出现损伤的部位,常常伴随着肾小管转运体的变化。有鉴于此,我们发现了一种肾小管转运体的内源性底物,它可以作为早期检测药物性 AKI 的生物标记物。通过使用庆大霉素(GEN)和万古霉素(VCA)诱导的 AKI 模型,我们发现在这两种 AKI 模型中,末端代谢物创伤酸(TA)都迅速增加。TA是一种高度白蛋白结合的化合物(96%-100%),不能被肾小球过滤,主要通过OAT1、OAT3、OATP4C1和P-gp转运体由肾小管排出。重要的是,血清 TA 水平升高与 OAT1 和 OAT3 水平降低之间存在相关性。一项临床研究显示,在重症监护室(ICU)环境中,20 名 AKI 患者中有 13 人的血清 TA 水平先于血清肌酐(SCr)的升高而升高。此外,肾病综合征、慢性肾功能衰竭和急性肾功能衰竭患者的血清中 TA 水平也明显升高。这些结果表明,在药物诱导的 AKI 期间,肾小管转运体表达的减少会导致血清 TA 水平的升高,TA 的变化可作为肾小管损伤的监测指标。
Identification of a substrate of the renal tubular transporters for detecting drug-induced early acute kidney injury.
Early identification of drug-induced acute kidney injury (AKI) is essential to prevent renal damage. The renal tubules are typically the first to exhibit damage, frequently accompanied by changes in renal tubular transporters. With this in mind, we have identified an endogenous substrate of the renal tubular transporters that may serve as a biomarker for early detection of drug-induced AKI. Using gentamicin (GEN) and vancomycin (VCA)-induced AKI models, we found that traumatic acid (TA), an end metabolite, was rapidly increased in both AKI models. TA, a highly albumin-bound compound (96%-100%), could not be filtered by the glomerulus and was predominantly eliminated by renal tubules via the OAT1, OAT3, OATP4C1, and P-gp transporters. Importantly, there is a correlation between elevated serum TA levels and reduced OAT1 and OAT3 levels. A clinical study showed that serum TA levels rose before an increase in serum creatinine (SCr) in thirteen out of twenty AKI patients in an intensive care unit (ICU) setting. In addition, there was a notable rise in TA levels in the serum of individuals suffering from nephrotic syndrome, chronic renal failure, and acute renal failure. These results indicate that the decrease in renal tubular transporter expression during drug-induced AKI leads to an increase in the serum TA level, and the change in TA may serve as a monitor for renal tubular injury.
期刊介绍:
The mission of Toxicological Sciences, the official journal of the Society of Toxicology, is to publish a broad spectrum of impactful research in the field of toxicology.
The primary focus of Toxicological Sciences is on original research articles. The journal also provides expert insight via contemporary and systematic reviews, as well as forum articles and editorial content that addresses important topics in the field.
The scope of Toxicological Sciences is focused on a broad spectrum of impactful toxicological research that will advance the multidisciplinary field of toxicology ranging from basic research to model development and application, and decision making. Submissions will include diverse technologies and approaches including, but not limited to: bioinformatics and computational biology, biochemistry, exposure science, histopathology, mass spectrometry, molecular biology, population-based sciences, tissue and cell-based systems, and whole-animal studies. Integrative approaches that combine realistic exposure scenarios with impactful analyses that move the field forward are encouraged.