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Inhibition of hypoxia-inducible factor-prolyl hydroxylation protects from
cyclophosphamide-induced bladder injury and urinary dysfunction.
Clayton DB, Tong CMC, Li B, Taylor AS, De S, Mason MD, Dudley AG, Davidoff O,
Kobayashi H, Haase VH
Submitted Externally on 6/21/2022
American journal of physiology. Renal physiology
Volume : Pages
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 (DMOG) or molidustat, two small
molecule inhibitors of HIF-prolyl hydroxylases (HIF-PHIs), profoundly mitigated
CYP-induced bladder injury and inflammation as assessed by morphologic analysis
of transmural edema and urothelial integrity and by measuring tissue cytokine
expression. Void spot analysis to examine bladder function quantitatively
demonstrated that HIF-PHI administration normalized micturition patterns and
protected against CYP-induced alteration of urinary frequency and micturition
patterns. Our studies highlight 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.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
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