Pharmacological HIF-1 activation upregulates extracellular vesicle production synergistically with adiponectin through transcriptional induction and protein stabilization of T-cadherin

Pharmacological activation of hypoxia-inducible factor 1alpha (HIF-1α), a hypoxia-responsive transcription factor, has attracted increasing attention due to its efficacy not only in renal anemia but also in various disease models. Our study demonstrated that a HIF-1 activator enhanced exosome production from cultured endothelial cells synergistically with adiponectin, an adipocyte-derived factor, through both transcriptional induction and posttranscriptional stabilization of an adiponectin binding partner, T-cadherin. Increased exosome levels were observed in wild-type mice but not in T-cadherin null mice after consecutive administration of roxadustat. Adiponectin- and T-cadherin-dependent increased exosome production may be involved in the pleiotropic effects of HIF-1 activators.