Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Activation of the
oxygen-regulated
hypoxia-inducible factor (HIF) pathway has been shown to protect mucosal membranes by increasing the expression of cytoprotective genes and by suppressing
inflammation. The activity of HIF is controlled by
prolyl hydroxylase domain (PHD)
dioxygenases, which have been exploited as therapeutic targets for the treatment of
anemia of
chronic kidney disease. Here, we established a mouse model of acute
cyclophosphamide (CYP)-induced blood-urine barrier disruption associated with
inflammation and severe urinary dysfunction to investigate the HIF-PHD axis in inflammatory bladder injury. We found that systemic administration of
dimethyloxalylglycine or
molidustat, two small-molecule inhibitors of HIF-
prolyl hydroxylases, profoundly mitigated CYP-induced bladder injury and
inflammation as assessed by morphological analysis of transmural
edema and urothelial integrity and by measuring tissue
cytokine expression. Void spot analysis to examine bladder function quantitatively demonstrated that HIF-
prolyl hydroxylase inhibitor administration normalized micturition patterns and protected against CYP-induced alteration of urinary frequency and micturition patterns. Our study highlights the therapeutic potential of HIF-activating small-molecule compounds for the prevention or
therapy of bladder injury and urinary dysfunction due to blood-urine barrier disruption.NEW & NOTEWORTHY Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Here, we demonstrate that pharmacological inhibition of
hypoxia-inducible factor (HIF)-prolyl hydroxylation prevented bladder injury and protected from urinary dysfunction in a mouse model of
cyclophosphamide-induced disruption of the blood-urine barrier. Our study highlights a potential role for HIF-activating small-molecule compounds in the prevention or
therapy of bladder injury and urinary dysfunction and provides a rationale for future clinical studies.