The glomerulus, the basic filtration unit of the kidney, is a complex network of capillaries. Capillaries are tiny blood vessels that control the movement of ions, water, and metabolites while remaining impermeable to essential macromolecules such as proteins. The selectively permeable capillary wall is known as the glomerular filtration barrier (GFB) and is made up of three main components: glomerular endothelial cells (GEnCs), glomerular basement membrane, and podocytes. GEnCs line the inner surface of the capillary wall and are covered with a thin layer of glycoproteins and other carbohydrate-based moieties.
Adhesion G protein-coupled receptor F5 (ADGRF5), a transmembrane cell receptor expressed in GEnC, has been suggested to affect GFB integrity and may play a role in its structural and functional maintenance. To elucidate the exact role of ADGRF5 in maintaining GFB integrity, a collaborative research investigation was conducted by scientists from Tokyo Institute of Technology (Tokyo Tech) and Kyorin University. The results of their study were published in the Journal of the American Society of Nephrology on June 6, 2024.
A research team led by Associate Professor Nobuhiro Nakamura of the School of Life Science and Technology, Tokyo Institute of Technology, and Professor Miki Nagase of the Department of Anatomy, Kyorin University School of Medicine, conducted a series of gene knockout and knockdown experiments in primary mouse and human GEnCs to investigate the specific role and underlying mechanism of ADGRF5 in maintaining GFBs.
Dr. Nakamura explained the motivation for this study: “Using the Nephroseq v5 database, we analyzed kidney gene expression profiles and found that ADGRF5 mRNA expression was decreased in the glomeruli of patients with diabetic nephropathy. Furthermore, there was a positive correlation between glomerular ADGRF5 expression and estimated glomerular filtration rate.”
The researchers initially observed specific expression of ADGRF5 within endothelial cells of the glomerular capillary wall. In mice with a genetic knockout of ADGRF5, the GFB was affected by morphological abnormalities, including splitting and thickening of the glomerular basement membrane and GEnC detachment. The overall integrity of the GFB was severely affected, resulting in albuminuria (the presence of albumin protein in the urine).
Furthermore, ADGRF5 gene deletion and knockdown in mouse and human primary GEnCs altered the expression of genes important for maintaining GFB integrity. Specifically, ADGRF5 knockout/knockdown significantly downregulated type IV collagen (Col4a3 and Col4a4), which constitutes the GFB and influences GFB permeability. In addition, Krüppel-like factor 2 (KLF2), a mechanosensitive transcription factor that controls endothelial cell function, was upregulated.
Taken together, their findings highlight the important role that ADGRF5 plays in maintaining the integrity of the GFB. Dr. Nakamura highlighted the potential impact of this study, saying, “This study has revealed a new mechanism that maintains the GFB. Insights into the role of ADGRF5 will aid in our understanding of glomerular diseases and greatly contribute to future research advances.”
Elucidating the novel function of the ADGRF5 receptor is expected to lead to the discovery of innovative therapies for the treatment of glomerular filtration barrier dysfunction, particularly proteinuria.
sauce:
Tokyo Institute of Technology
Journal References:
DOI: 10.1681/ASN.00000000000000427