Low-dose angiotensin AT receptor β-arrestin-biased ligand, TRV027, protects against cisplatin-induced nephrotoxicity.

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 AT 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 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).

CONCLUSION

Low-dose TRV027 may offer potential benefits in kidney injury due to cisplatin.