CD239 deficiency in distal tubules impairs cell polarity and increases susceptibility to renal injury

Abstract

CD239, also known as Lutheran blood group glycoprotein (Lu) or basal cell adhesion molecule (B-CAM), is a transmembrane protein belonging to the immunoglobulin superfamily (IgSF). CD239 serves as a specific receptor for laminin 5, a subunit of laminin-511/-521, which are major components of renal basement membranes. A previous study of another group demonstrated that CD239-null mice are healthy and develop normally. Although no alteration in renal function was observed, most glomeruli in the mutant kidneys exhibited morphological abnormalities. In this study, we investigated the role of CD239 in renal tubules. We examined the distribution of CD239 using renal tubule-specific markers. CD239 was localized to the Henle's loop, distal tubule, and collecting duct, but not to the proximal tubule. Next, we analyzed the localization of renal tubular molecules in CD239-null mice. The localization of uromodulin (UMOD) and Na-K-Cl cotransporter (NKCC2) was disrupted in the distal tubules lacking CD239, suggesting that CD239 plays a role in maintaining the polarity of renal epithelial cells. Furthermore, to examine the stability of the distal tubules, CD239-null mice were subjected to chronic kidney disease (CKD) using an adenine-rich diet. Blood analysis revealed that CD239-null mice fed an adenine diet readily developed CKD. Adenine-fed null mice exhibited more marked histological injury along the distal tubules compared to that by controls. These results indicate that CD239 is essential not only for maintaining cellular polarity but also for ensuring the stability of the distal tubules. Although CD239-null humans exhibit no obvious associated pathology, it could be a predisposition to CKD.