Adhesion GPCRs in Kidney: New Insights into Development, Physiology and Disease

Recently, adhesion G-protein-coupled receptors (aGPCRs) gained recognition for their essential roles in embryonic development. However, for the majority of them, their exact functions and underlying signaling mechanisms remain poorly understood. Here, we summarize the existing literature on aGPCRs in the context of kidney development, physiology, and disease. We compile available aGPCR expression profiles, discuss their validation statuses, and describe the knockout phenotypes. For instance, Celsr1/Adgrc1 is expressed early in metanephric development, and its deletion results in aberrant oriented cell division and simplified ureteric trees. Furthermore, GPR116/ADGRF5 is important for the integrity of the glomerular filtration barrier and regulation of renal acid secretion. Several aGPCRs are also implicated in kidney diseases, e.g., deletion of Gpr56/Adgrg1 ameliorates diabetic kidney disease. On the other hand, upregulation of GPR97/ADGRG3 exacerbates acute kidney injury and hypertensive nephropathy. Notably, for around two-thirds of the aGPCRs expressed in the kidney, no function has been proposed. For such aGPCRs, we draw hypotheses for potential functions based on their role in other tissues. Our goal is to shed light on how aGPCRs potentially contribute to the complex and highly regulated orchestration of cellular and molecular mechanisms underlying disease and development of a highly specialized organ such as the kidney.