Adhesion G protein-coupled receptor F5 (ADGRF5) mediates shear stress mechanotransduction in glomerular endothelial cells

Adhesion G protein-coupled receptor F5 (ADGRF5) is widely expressed and is involved in various physiological and pathophysiological functions. ADGRF5 has been demonstrated to be expressed in glomerular endothelial cells and to maintain the integrity of the glomerular filtration barrier by regulating the expression of type IV collagens COL4A3 and COL4A4. However, the mechanisms underlying its activation remain unclear. Herein, we showed that ADGRF5 overexpression enhances ERK1/2 phosphorylation induced by laminar flow shear stress in human embryonic kidney PEAKrapid cells. Inhibitor and knockdown experiments revealed that the ADGRF5-mediated shear stress response proceeds via the Gαq/11-protein kinase C-RAF1-MEK1/2-ERK1/2 cascade. Mutagenesis analyses showed that shear flow-mediated activation of ADGRF5 requires the tethered agonist (Stachel) sequence and the C-terminal helix 8. Consistent with the overexpression analyses, endogenous ADGRF5 mediated shear stress-induced ERK1/2 signaling in human primary renal glomerular endothelial cells. Moreover, ADGRF5 knockdown attenuated shear flow-induced upregulation of the immediate early response genes and the type IV collagen genes COL4A3 and COL4A4. These results suggest that ADGRF5 mediates shear stress mechanotransduction in glomerular endothelial cells and regulates endothelial cell responses, with potential implications for glomerular filtration barrier homeostasis.