β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis

Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between the two types of cells. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that exosomes were aroused by beta-catenin in renal tubular cells. Osteopontin (OPN), especially its N-terminal fragment (N-OPN), was encapsulated in beta-catenin-controlled tubular cell-derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of beta-catenin in tubular cells (Ksp-beta-catenin(-/-)) or gene ablation of CD44 (CD44(-/-)) greatly ameliorated renal fibrosis. Notably, N-OPN was carried by exosome and secreted into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome-mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by beta-catenin.

Automated summary

The activation of beta-catenin in renal tubular cells leads to the release of exosomes containing osteopontin (OPN) that are then taken up by fibroblasts, promoting their proliferation and activation through binding with CD44. Deletion of beta-catenin or CD44 greatly improves renal fibrosis. N-terminal fragment of OPN is secreted into the urine and negatively correlated with kidney function in CKD patients. Urinary exosomes from CKD patients accelerate renal fibrosis, which can be blocked by CD44 deletion.