Role of GPR84 in Kidney Injury in a Surrogate COVID-19 Mouse Model

Abstract

40% of severe acute respiratory syndrome coronavirus two (SARS-CoV-2) severe cases develop acute kidney injury (AKI). Current treatment for renal complications limits financial and material resources available. To explore alternative treatments and accelerate research in case of future coronavirus outbreaks, a mouse model of coronavirus disease 2019-associated AKI (C19-AKI) would represent a critical biomedical research tool. The surrogate model of C19-AKI (SMC) developed consisted of angiotensin-converting enzyme two (ACE2) knockout (KO) mice receiving 400 ng/kg/min of angiotensin (Ang) II by osmotic minipump for eight days with a single injection of lipopolysaccharide (LPS; 10 mg/kg) on the seventh day of Ang II and euthanasia 24 hours after LPS. Similarly, to C19-AKI, the SMC exhibited albuminuria, elevated blood urea nitrogen, electrolyte imbalance, neutrophil infiltration, and upregulation of the G-coupled protein receptor (GPR)84 and pro-inflammatory and injury markers. GPR84 was found in bronchoalveolar lavage fluid neutrophils of coronavirus disease 2019 (COVID-19) patients, suggesting a potential implication of GPR84 in the disease. We hypothesised that GPR84 deletion or antagonism with GLPG-1205 could attenuate SMC’s indices of renal injury and inflammation. GLPG-1205 and GPR84 KO had no effects in the SMC model, as suggested by unchanged albuminuria, electrolytes, and markers expression. Interestingly, neutrophil infiltration was attenuated by GLPG-1205 only. The SMC is an interesting tool for therapeutic development for infections associated with renal injury, such as SARS-CoV-2. GPR84 role in the SMC needs to be further assessed.