Glomerular Endothelial Cell Receptor ADGRF5 and the Integrity of the Glomerular Filtration Barrier

Key Points Deletion of endothelial receptor adhesion G-protein–coupled receptor F5 in mice led to abnormal structural and functional properties of the glomerular filtration barrier. Adhesion G-protein–coupled receptor F5 regulates gene expression of glomerular basement membrane components and a mechanosensitive transcription factor. Background Glomerular endothelial cells are recognized to be important for maintaining the glomerular filtration barrier. Adhesion G-protein–coupled receptor F5 (ADGRF5), an adhesion G protein–coupled receptor, has been suggested to be involved in endothelial cell function. However, the role of ADGRF5 in the glomerular filtration barrier integrity remains elusive. Methods Cellular expression of ADGRF5 in mouse glomerulus was determined by histological analyses. The effect of ADGRF5 deletion on the glomerular morphology, kidney function, and glomerular endothelial gene/protein expression was then analyzed using ADGRF5 knockout ( Adgrf5 −/− ) mice and human primary glomerular endothelial cells. Results ADGRF5 was specifically expressed in the capillary endothelial cells within the glomerulus. Adgrf5 −/− mice developed albuminuria and impaired kidney function with morphological defects in the glomeruli, namely glomerular hypertrophy, glomerular basement membrane splitting and thickening, diaphragmed fenestration and detachment of the glomerular endothelial cells, and mesangial interposition. These defects were accompanied by the altered expression of genes responsible for glomerular basement membrane organization (type 4 collagens and laminins) and Krüppel-like factor 2 ( Klf2 ) in glomerular endothelial cells. Moreover, ADGRF5 knockdown decreased COL4A3 and COL4A4 expression and increased KLF2 expression in human primary glomerular endothelial cells. Conclusions The loss of ADGRF5 resulted in altered gene expression in glomerular endothelial cells and perturbed the structure and permselectivity of the glomerular filtration barrier.