Low-Dose Angiotensin At1 Receptor Β-Arrestin-Biased Ligand, Trv027, Protects Against Cisplatin-Induced Nephrotoxicity Publisher Pubmed



Esmaeeli A¹ ; Ebrahimi F¹ ; Tanha K² ; Assadi M³ ; Seyedabadi M^{4, 5}
Source: Pharmacological Reports Published:2020

Abstract

Background: 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 AT1 receptor β-arrestin-biased ligand, as well as losartan and valsartan on cisplatin-induced kidney injury. Method: 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. Results: 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 AT1 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). Conclusion: Low-dose TRV027 may offer potential benefits in kidney injury due to cisplatin. © 2020, Maj Institute of Pharmacology Polish Academy of Sciences.