Abstract: FR-PO1218
Exploring the Role of the Acid-Sensing Receptor GPR4 in Progression of Kidney Diseases
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Yang, Li, East Carolina University Brody School of Medicine, Greenville, North Carolina, United States
- Swyers, Madison M, East Carolina University Brody School of Medicine, Greenville, North Carolina, United States
- Traylor, Amie, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Agarwal, Anupam, University of Alabama at Birmingham, Birmingham, Alabama, United States
- DuBose, Thomas D., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
Background
Although early-stage chronic kidney disease (CKD) is most often asymptomatic, retention of acid derived from the metabolism of a diet high in protein has been recognized as an important risk factor for the progression of CKD and eventual kidney failure. Chronic acid stress in the kidney causes a “maladaptive” response, exacerbating renal inflammation, fibrosis, and CKD progression. Therefore, it is important to elucidate the mechanisms by which the kidney responds to acid stress and to develop innovative mechanism-based therapeutic approaches for impeding progression of CKD. GPR4 is an acid-sensing pro-inflammatory GPCR that stimulates the expression of inflammatory and stress response genes and increases leukocyte infiltration. Inhibition of GPR4 can alleviate arthritis, colitis, and ischemia-reperfusion injury in animal models without overt side effects. However, the role of GPR4 in CKD is not fully understood.
Methods
In this study, the aristolochic acid (AA)-induced nephropathy model was employed in the mouse. Immunohistochemistry and quantitative RT-PCR were utilized to measure the expression of GPR4 and inflammation and fibrosis genes and assess the infiltration of macrophages and T cells in AA-treated and control mouse kidneys.
Results
We demonstrate that GPR4 is highly expressed in endothelial cells of glomerular and peritubular capillaries and afferent/efferent arterioles, with lower expression in renal tubule epithelial cells. Moreover, GPR4 expression was increased in AA-treated mouse kidneys as compared to vehicle controls and correlated positively with the expression of inflammation and fibrosis genes such as TNF-α, IFN-γ, E-selectin, CXCL2, and COL1A1. Immunohistochemistry reveals that the infiltration of F4/80+ macrophages, CD4+ T cells, and CD8+ T cells, and the expression of the acid stress marker LAMP2 are substantially increased in AA mouse kidneys.
Conclusion
Our results suggest that GPR4 plays a role in the inflammatory and fibrotic responses of the kidney in the AA-induced CKD mouse model. Additional studies using GPR4 knockout mice and GPR4 inhibitors are needed to further elucidate the role of GPR4 in progression of kidney disease and to explore GPR4 antagonism as a novel approach for slowing progression of loss of kidney function.
Funding
- NIDDK Support