Role of Hypoxia Inducible Factor-1α (HIF-1α) in Innate Defense against Uropathogenic Escherichia coli Infection.
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.
Division of Pediatric Pharmacology & Drug Discovery, University of California, San Diego, La Jolla, California, United States of America.
Ann E
AE
Lin
Division of Pediatric Pharmacology & Drug Discovery, University of California, San Diego, La Jolla, California, United States of America.
Federico C
FC
Beasley
Division of Pediatric Pharmacology & Drug Discovery, University of California, San Diego, La Jolla, California, United States of America.
Joshua
J
Olson
Division of Pediatric Pharmacology & Drug Discovery, University of California, San Diego, La Jolla, California, United States of America.
Nadia
N
Keller
Aerpio Therapeutics, Cincinnati, Ohio, United States of America.
Robert A
RA
Shalwitz
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Thomas J
TJ
Hannan
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Scott J
SJ
Hultgren
Division of Pediatric Pharmacology & Drug Discovery, University of California, San Diego, La Jolla, California, United States of America; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America; Rady Children's Hospital, San Diego, California, United States of America.
Victor
V
Nizet
D000283:Administration, Intravesical; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000819:agonists / Q000378:metabolism; D001422:Bacterial Adhesion / Q000187:drug effects; D002460:Cell Line; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000517:prevention & control; D005260:Female; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D055550:Protein Stability / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D014552:Urinary Tract Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000517:prevention & control; D056689:Uropathogenic Escherichia coli / Q000187:drug effects / Q000276:immunology*; D019459:Urothelium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology
C575838:AKB-4924; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010879:Piperazines; D011728:Pyridones; D012333:RNA, Messenger; D009569:Nitric Oxide