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Low-dose angiotensin AT1 receptor β-arrestin-biased ligand, TRV027, protects against cisplatin-induced nephrotoxicity

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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.

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Funding

The study was supported by the deputy of research of Bushehr University of Medical Sciences. We are grateful to Dr. Jonathan Violin for fruitful discussion about pharmacological profile of angiotensin receptor modulators, especially TRV027. We thank Tehrandaru pharmaceutical company for providing losartan and valsartan APIs, and Dr. Kiarash Tanha for his consult on statistical analysis.

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Contributions

A.E. performed pathological examinations, F.E. performed animal experiments, prepared serum and tissue samples, M.A. and K.T. conducted scintigraphy experiments, and M.S. developed the idea, supervised the experiments, analyzed the data, and wrote the paper.

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Correspondence to Mohammad Seyedabadi.

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Esmaeeli, A., Ebrahimi, F., Tanha, K. et al. Low-dose angiotensin AT1 receptor β-arrestin-biased ligand, TRV027, protects against cisplatin-induced nephrotoxicity. Pharmacol. Rep 72, 1676–1684 (2020). https://doi.org/10.1007/s43440-020-00172-5

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  • DOI: https://doi.org/10.1007/s43440-020-00172-5

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