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

Area of Science:

• Pharmacology
• Nephrology
• Cell Signaling

Background:

• Beta-arrestin recruitment to G protein-coupled receptors (GPCRs) plays active roles in cell signaling, beyond initial descriptions of receptor desensitization.
• The study investigates TRV027, a novel beta-arrestin-biased ligand for the angiotensin AT1 receptor, alongside established blockers losartan and valsartan.
• Cisplatin is a widely used chemotherapy agent known to cause significant kidney injury.

Purpose of the Study:

• To evaluate the efficacy of TRV027, losartan, and valsartan in mitigating cisplatin-induced kidney injury in a rat model.
• To determine the dose-dependent effects of TRV027 on renal function and histopathology following cisplatin treatment.
• To compare the protective potential of a beta-arrestin-biased AT1 receptor ligand with traditional AT1 receptor blockers in the context of chemotherapy-induced nephrotoxicity.

Main Methods:

• Male Sprague-Dawley rats were administered varying doses of angiotensin receptor ligands (TRV027, losartan, valsartan) with or without cisplatin.
• Kidney injury was assessed using multiple parameters including renal radiotracer uptake (DMSA), histopathology, serum biomarkers (BUN, creatinine), and electrolyte levels (Na+, K+).
• Animal SPECT imaging was employed to monitor renal function non-invasively.

Main Results:

• TRV027, losartan, and valsartan alone did not affect baseline kidney function or histology.
• Co-administration with cisplatin aggravated kidney injury markers at higher doses for losartan and valsartan, though hypokalemia was improved.
• Low-dose TRV027 (1 mg/kg/day) demonstrated protective effects against cisplatin-induced nephrotoxicity, improving radiotracer uptake, kidney histology, BUN, creatinine, and electrolyte balance, while higher doses were ineffective.

Conclusions:

• Low-dose TRV027 exhibits potential therapeutic benefits in preventing or treating cisplatin-induced kidney injury.
• The findings suggest a differential role for beta-arrestin signaling in mediating the renal protective effects of AT1 receptor ligands.
• Further investigation into the specific mechanisms of low-dose TRV027 is warranted for clinical translation in managing chemotherapy-related nephrotoxicity.