Impaired wound healing in hypoxic renal tubular cells: roles of hypoxia-iducible factor-1 and glycogen synthase kinase 3B/Bcatenin signaling

Wound and subsequent healing are frequently associated with hypoxia. Although hypoxia induces angiogenesis for tissue re-modeling during wound healing, it may also affect the healing response of parenchymal cells. Whether and how wound heal-ing is affected by hypoxia in kidney cells and tissues is currently unknown. Here, we used scratch-wound healing and transwell migration models to examine the effect of hypoxia in cultured renal proximal tubular cells (RPTC). Wound healing and migra-tion were significantly slower in hypoxic (1 % oxygen) RPTC than normoxic (21 % oxygen) cells. Hypoxia-inducible factor-1 (HIF-1) was induced during scratch-wound healing in nor-moxia, and the induction was more evident in hypoxia. Never-theless, HIF-1-null and wild-type cells healed similarly after scratch wounding. Moreover, activation of HIF-1 with di-methyloxalylglycine in normoxic cells did not suppress wound healing, negating a major role of HIF-1 in wound healing in this model. Scratch-wound healing was also associated with gly-cogen synthase kinase 3 (GSK3)/-catenin signaling, which was further enhanced by hypoxia. Pharmacological inhibition of GSK3 resulted in -catenin expression, accompanied by the suppression of wound healing and transwell cell migration. Ectopic expression of -catenin in normoxic cells could also suppress wound healing, mimicking the effect of hypoxia. Con-versely, inhibition of -catenin via dominant negative mutants or short hairpin RNA improved wound healing and transwell migration in hypoxic cells. The results suggest that GSK3/-catenin signaling may contribute to defective wound healing in hypoxic renal cells and tissues