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

Fujii K., Fujishima Y., Kita S., et al. Pharmacological HIF-1 activation upregulates extracellular vesicle production synergistically with adiponectin through transcriptional induction and protein stabilization of T-cadherin. Scientific Reports 14, 3620 (2024); https://doi.org/10.1038/s41598-024-51935-6.Pharmacological activation of hypoxia-inducible factor 1 (HIF-1), 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 extracellular vesicle (EV) 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 EV 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 EV production may be involved in the pleiotropic effects of HIF-1 activators

Soluble T-cadherin secretion from endothelial cells is regulated via insulin/PI3K/Akt signalling

Okita T., Kita S., Fukuda S., et al. Soluble T-cadherin secretion from endothelial cells is regulated via insulin/PI3K/Akt signalling. Biochemical and Biophysical Research Communications 732, 150403 (2024); https://doi.org/10.1016/j.bbrc.2024.150403.Aim and objective: Our recent report showed that soluble T-cadherin promotes pancreatic beta-cell proliferation. However, how and where the secretion of soluble T-cadherin is regulated remain unclear. Methods and results: Soluble T-cadherin levels significantly increased in leptin receptor-deficient db/db mice with hypoinsulinaemia or in wild-type mice treated with insulin receptor blockade by S961. Similar results were observed in human subjects; Diabetic ketoacidosis patients at the time of hospitalization had increased plasma soluble T-cadherin levels, which decreased after insulin infusion therapy. Patients with recurrent ovarian cancer who were administered a phosphatidylinositol-3 kinase (PI3K)-alpha inhibitor (a new anticancer drug) had increased plasma soluble T-cadherin and plasma C-peptide levels. Endothelial cell-specific T-cadherin knockout mice, but not skeletal muscle- or cardiac muscle-specific T-cadherin knockout mice, showed a 26 % reduction in plasma soluble T-cadherin levels and a significant increase in blood glucose levels in streptozocin-induced diabetes. The secretion of soluble T-cadherin from human endothelial cells was approximately 20 % decreased by insulin and this decrease was canceled by blockade of insulin receptor/Akt signalling, not Erk signalling. Conclusion: We conclude that insulin regulates soluble T-cadherin levels and soluble T-cadherin secretion from endothelial cells is positively regulated by insulin/insulin receptor/Akt signalling

Coincidence of Large Adrenal Cyst and Prominent Hyporeninemic Hyperaldosteronism

A 67-year-old Japanese woman who had end-stage renal disease was referred to our hospital for kidney transplantation. Abdominal CT revealed a large adrenal mass with inhomogeneity. She had a history of hospitalization for stroke and heart failure and exhibited prominent hyporeninemic hyperaldosteronism. Histological examination of the resected tumor with anti-CYP11B2 antibody indicated that she had a vascular endothelial cyst with primary aldosteronism (PA) due to multiple adrenocortical micronodules. This report implicates the pathological interaction between adrenal vascular cysts and PA-mediated vascular damage of the adrenal vein