Loss of GPR56 in the kidney promotes adenine-induced renal injury

Gpr56 is a multifunctional adhesin G protein-coupled receptor involved in diverse biological processes, including neurodevelopment and disease, immune regulation, reproduction, hemostasis, and tumorigenesis. The role of Gpr56 in the kidney has been understudied. A recent study shows that Gpr56 in the glomerular endothelial cells promotes diabetic kidney disease progression via regulation of eNOS. Using RNAscope in situ hybridization (ISH), we detected ubiquitous expression of Gpr56 mRNA along the renal tubules, with high expression in the proximal tubule, loop of Henle and collecting duct, but no expression in glomeruli. To investigate the physiological role of Gpr56 in the kidney, we generated a whole kidney-specific Gpr56 knockout (Gpr56 KS-KO ) mouse model by crossing Gpr56 flox (Control, Con) with Pax8 Cre mice. RNAscope ISH confirmed Gpr56 deletion across all nephron segments in Gpr56 KS-KO mice. These mice were born at predicted Mendelian frequencies, appeared grossly indistinguishable from Con mice, and developed normally. For baseline phenotypic characterization, we found no differences in urine osmolality (2072±48 vs 2092±51 mOsm/kg, NS ), urine pH (5.59±0.05 vs 5.63±0.04, NS ), blood pH (7.18±0.02 vs 7.18±0.02, NS ), blood HCO 3 - (12.01±0.58 vs 13.36±0.41 mmol/L, NS ), blood Na + (146.7±0.3 vs 145±0.5 mmol/L, NS ), or blood K + (4.07±0.08 vs 4.14±0.09 mmol/L, NS ) between Con (n=9, males) and Gpr56 KS-KO mice (n=9, males). In addition, no difference was found in glomerular filtration rate (GFR) (774±38 vs 667±66 ml/min/100g BW) between Con (n=3, males) and Gpr56 KS-KO mice (n=4, males) in baseline. When challenged with adenine (100 mg/kg BW/d) for 2 weeks by oral gavage, both control and Gpr56 KS-KO mice show a significant drop in GFR. However, GFR remains significantly lower (515±59 vs 189±58 ml/min/100g BW, P < 0.01) in Gpr56 KS-KO mice compared to control mice. Two weeks post adenine treatment, Gpr56 KS-KO mice exhibit a trend of lower GFR (684±49 vs 502±83 ml/min/100g BW, P = 0.06) compared to Con mice. These findings suggest that Gpr56 might play a protective role against GFR decline in adenine-induced renal injury. In conclusion, we successfully generated kidney-specific GPR56 knockout mouse model and demonstrated that loss of Gpr56 in the kidney exacerbates adenine-induced renal injury. Future studies will investigate the underlying mechanisms and evaluate Gpr56 as a potential therapeutic target for kidney diseases. R00DK127215 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.