Department of Pathology, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran.
Department of Medical Physics and Biomedical Engineering, Tehran University of Medical Sciences, Tehran, Iran.
Pharmacol Rep. 2020 Dec;72(6):1676-1684. doi: 10.1007/s43440-020-00172-5. Epub 2020 Oct 22.
Recruitment of β-arrestin to G protein-coupled receptors (GPCRs), initially described to cause receptor desensitization, has recently been shown to take active roles in cell signaling. We investigated the effects of TRV027, an angiotensin AT receptor β-arrestin-biased ligand, as well as losartan and valsartan on cisplatin-induced kidney injury.
Male Sprague-Dawley rats were treated with angiotensin receptor ligands (1 or 10 mg/kg/day) with or without cisplatin, and kidney variables were monitored using animal SPECT, histopathology, and serum parameters.
TRV027, losartan, and valsartan did not alter renal dimercaptosuccinic acid (DMSA) uptake, histopathological manifestations of kidney injury, blood urea nitrogen (BUN), and creatinine or Na and K levels, per se. However, when rats co-treated with cisplatin and either of the AT receptor blockers at higher doses, we observed aggravation of cisplatin-induced reduction of radiotracer uptake but improvement of cisplatin-induced hypokalemia, and insignificant effect on histological findings. Furthermore, we noted an additional increase in cisplatin-induced augmentation of BUN and creatinine levels in cisplatin plus valsartan group. TRV027 (1 mg/kg/day) inhibited cisplatin adverse effects on radiotracer uptake, kidney histology, BUN, and creatinine as well as electrolyte levels, but it failed to produce protective effects at higher dose (10 mg/kg/day).
Low-dose TRV027 may offer potential benefits in kidney injury due to cisplatin.
最初被描述为导致受体脱敏的β-arrestin 与 G 蛋白偶联受体（GPCR）的募集，最近已被证明在细胞信号转导中发挥积极作用。我们研究了 TRV027（一种血管紧张素 AT 受体β-arrestin 偏向配体）以及氯沙坦和缬沙坦对顺铂诱导的肾损伤的影响。
雄性 Sprague-Dawley 大鼠用血管紧张素受体配体（1 或 10mg/kg/天）处理，并用或不用顺铂，并用动物 SPECT、组织病理学和血清参数监测肾脏变量。
TRV027、氯沙坦和缬沙坦本身并不改变二巯丁二酸（DMSA）摄取、肾损伤的组织病理学表现、血尿素氮（BUN）和肌酐或 Na 和 K 水平。然而，当大鼠与更高剂量的 AT 受体阻滞剂共同用顺铂治疗时，我们观察到顺铂诱导的示踪剂摄取减少加剧，但顺铂诱导的低钾血症改善，对组织学发现无明显影响。此外，我们注意到在顺铂加缬沙坦组中，顺铂诱导的 BUN 和肌酐水平的额外增加。TRV027（1mg/kg/天）抑制了顺铂对示踪剂摄取、肾组织学、BUN 和肌酐以及电解质水平的不良影响，但在高剂量（10mg/kg/天）时未能产生保护作用。
低剂量 TRV027 可能对顺铂引起的肾损伤有益。
