Abstract
Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infections (UTI) affecting approximately 150 million people worldwide. Here, we revealed the importance of transcriptional regulator hypoxia-inducible factor-1 α subunit (HIF-1α) in innate defense against UPEC-mediated UTI. The effects of AKB-4924, a HIF-1α stabilizing agent, were studied using human uroepithelial cells (5637) and a murine UTI model. UPEC adherence and invasion were significantly reduced in 5637 cells when HIF-1α protein was allowed to accumulate. Uroepithelial cells treated with AKB-4924 also experienced reduced cell death and exfoliation upon UPEC challenge. In vivo, fewer UPEC were recovered from the urine, bladders and kidneys of mice treated transurethrally with AKB-4924, whereas increased bacteria were recovered from bladders of mice with a HIF-1α deletion. Bladders and kidneys of AKB-4924 treated mice developed less inflammation as evidenced by decreased pro-inflammatory cytokine release and neutrophil activity. AKB-4924 impairs infection in uroepithelial cells and bladders, and could be correlated with enhanced production of nitric oxide and antimicrobial peptides cathelicidin and β-defensin-2. We conclude that HIF-1α transcriptional regulation plays a key role in defense of the urinary tract against UPEC infection, and that pharmacological HIF-1α boosting could be explored further as an adjunctive therapy strategy for serious or recurrent UTI.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Intravesical
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Animals
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Anti-Bacterial Agents / administration & dosage
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Anti-Bacterial Agents / pharmacology
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Anti-Bacterial Agents / therapeutic use
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Antimicrobial Cationic Peptides / agonists
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Antimicrobial Cationic Peptides / metabolism
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Bacterial Adhesion / drug effects
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Cell Line
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Escherichia coli Infections / immunology
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Escherichia coli Infections / metabolism*
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Escherichia coli Infections / microbiology
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Escherichia coli Infections / prevention & control
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Female
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Host-Pathogen Interactions / drug effects
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / agonists
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Immunity, Innate* / drug effects
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Mice, Inbred C57BL
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Mice, Knockout
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Nitric Oxide / agonists
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Nitric Oxide / metabolism
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Piperazines / administration & dosage
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Piperazines / pharmacology
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Piperazines / therapeutic use
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Protein Stability / drug effects
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Pyridones / administration & dosage
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Pyridones / pharmacology
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Pyridones / therapeutic use
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RNA, Messenger / metabolism
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Urinary Tract Infections / immunology
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Urinary Tract Infections / metabolism*
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Urinary Tract Infections / microbiology
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Urinary Tract Infections / prevention & control
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Uropathogenic Escherichia coli / drug effects
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Uropathogenic Escherichia coli / immunology*
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Urothelium / drug effects
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Urothelium / immunology
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Urothelium / metabolism*
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Urothelium / microbiology
Substances
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AKB-4924
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Anti-Bacterial Agents
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Antimicrobial Cationic Peptides
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Piperazines
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Pyridones
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RNA, Messenger
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Nitric Oxide